U.S. patent application number 15/562381 was filed with the patent office on 2018-10-04 for tricyclic fused derivatives of 1-(cyclo)alkyl pyridin-2-one useful for the treatment of cancer.
This patent application is currently assigned to JUBILANT BIOSYS LIMITED. The applicant listed for this patent is JUBILANT BIOSYS LIMITED. Invention is credited to Murugan CHINNAPATTU, Pavan Kumar GONDRALA, Chandrika MULAKALA, Sridharan RAJAGOPAL, Dhanalakshmi SIVANANDHAN, Saravanan VADIVELU.
Application Number | 20180282345 15/562381 |
Document ID | / |
Family ID | 56015058 |
Filed Date | 2018-10-04 |
United States Patent
Application |
20180282345 |
Kind Code |
A1 |
VADIVELU; Saravanan ; et
al. |
October 4, 2018 |
TRICYCLIC FUSED DERIVATIVES OF 1-(CYCLO)ALKYL PYRIDIN-2-ONE USEFUL
FOR THE TREATMENT OF CANCER
Abstract
The present disclosure described heterocyclic compounds of
Formula I or, its stereoisomers, pharmaceutically acceptable salts,
complexes, hydrates, solvates, tautomers, polymorphs, racemic
mixtures, optically active forms and pharmaceutically active
derivative thereof and pharmaceutical compositions containing them
as the active ingredient. The present disclosure also describes the
synthesis and characterization of aforementioned compounds to
exhibit high anticancer activity. The compounds of the present
disclosure are useful as medicaments and their use in the
manufacture of medicaments for treatment, prevention or suppression
of diseases, and conditions mediated by one or more BET family of
bromodomains. ##STR00001##
Inventors: |
VADIVELU; Saravanan;
(Bangalore, IN) ; RAJAGOPAL; Sridharan;
(Bangalore, IN) ; CHINNAPATTU; Murugan;
(Bangalore, IN) ; GONDRALA; Pavan Kumar;
(Bangalore, IN) ; SIVANANDHAN; Dhanalakshmi;
(Bangalore, IN) ; MULAKALA; Chandrika; (Bangalore,
IN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
JUBILANT BIOSYS LIMITED |
Bangalore, |
|
IN |
|
|
Assignee: |
JUBILANT BIOSYS LIMITED
Bangalore,
IN
|
Family ID: |
56015058 |
Appl. No.: |
15/562381 |
Filed: |
March 30, 2016 |
PCT Filed: |
March 30, 2016 |
PCT NO: |
PCT/IN2016/050098 |
371 Date: |
September 27, 2017 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 471/04 20130101;
A61K 45/06 20130101; C07D 491/04 20130101; A61P 35/00 20180101;
A61K 2300/00 20130101 |
International
Class: |
C07D 491/04 20060101
C07D491/04; C07D 471/04 20060101 C07D471/04; A61P 35/00 20060101
A61P035/00 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 30, 2015 |
IN |
1636/CHE/2015 |
Claims
1. A compound of the Formula (I) ##STR00091## their analogs,
tautomeric forms, stereoisomer's, polymorphs, solvates,
intermediates, pharmaceutically acceptable salts, metabolites and
prodrugs thereof; wherein ---- is a single bond or a double bond; X
is selected from --O-- or --N--; n is 0-6; R.sub.1 is selected from
alkyl or cycloalkyl; R.sub.2 and R.sub.3 are independently selected
from hydrogen, halogen, hydroxy, nitro, cyano, azido, nitroso, oxo
(.dbd.O), thioxo (.dbd.S), --SO.sub.2--, amino, hydrazino, formyl,
alkyl, haloalkyl, alkoxy, haloalkoxy; arylalkoxy; cycloalkyl,
cycloalkyloxy, aryl, heterocyclyl, heteroaryl, alkylamino,
--COOR.sub.a, --C(O)R.sub.b, --C(S)R.sub.a, --C(O)NR.sub.aR.sub.b,
--C(S)NR.sub.aR.sub.b, --NR.sup.aC(O)NR.sub.bR.sub.c,
NR.sub.aC(S)NR.sub.bR.sub.c, --N(R.sub.a)SOR.sub.b,
--N(R.sub.a)SO.sub.2R.sub.b, --NR.sub.aC(O)OR.sub.b,
--NR.sub.aR.sub.b, --NR.sub.aC(O)R.sub.b--, NR.sub.aC(S)R.sub.b--,
--SONR.sub.aR.sub.b--, --SO.sub.2NR.sub.aR.sub.b--, --OR.sub.a,
--OR.sub.aC(O)OR.sub.b--, --OC(O)NR.sub.aR.sub.b, OC(O)R.sub.a,
--OC(O)NR.sub.aR.sub.b--, --R.sub.aNR.sub.bR.sub.c,
--R.sub.aOR.sub.b--, --SR.sub.a, --SOR.sub.a or --SO.sub.2R.sub.a,
wherein R.sub.a, R.sub.b and R.sub.c are independently selected
from hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl,
heteroaryl or hetroarylalkyl; R.sub.4 is selected from hydrogen,
alkyl, cycloalkyl, cyloalkenyl, cycloalkylalkyl, aryl, arylalkyl,
heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl or
haloalkyl; Z is selected from hydrogen, --CH.sub.2OR.sub.5,
--COOR.sub.5, --CONR.sub.5R.sub.6, --NHCOOR.sub.5, --NHCOR.sub.5 or
--NHSO.sub.2R.sub.5, R.sub.5 and R.sub.6 are independently selected
from hydrogen, hydroxyl, aryl, heteroaryl, cycloalkyl or alkyl.
2. The compound of the Formula (I) as claimed in claim 1, wherein
---- is a single bond or a double bond; X is selected from --O-- or
--N--; n is 0-1; R.sub.1 is selected from C.sub.1-C.sub.8 alkyl or
C.sub.3-C.sub.8cycloalkyl; R.sub.2 and R.sub.3 are independently
selected from hydrogen, fluoro, chloro, bromo, iodo, hydroxy,
nitro, cyano, azido, nitroso, oxo (.dbd.O), thioxo (.dbd.S),
--SO.sub.2--, amino, hydrazino, formyl, C.sub.1-C.sub.8alkyl,
C.sub.1-C.sub.8haloalkyl independently substituted with up to three
halogen selected from fluoro, chloro, bromo, or iodo,
C.sub.1-C.sub.8alkoxy, C.sub.1-C.sub.8haloalkoxy;
C.sub.5-C.sub.18arylalkoxy; C.sub.3-C.sub.8cycloalkyl,
C.sub.3-C.sub.8cycloalkyloxy, C.sub.5-C.sub.18aryl,
C.sub.2-C.sub.18heterocyclyl, C.sub.2-C.sub.18heteroaryl,
alkylamino, --COOR.sub.a, --C(O)R.sub.b, --C(S)R.sub.a,
--C(O)NR.sub.aR.sub.b, --C(S)NR.sub.aR.sub.b,
--NR.sup.aC(O)NR.sub.bR.sub.c, NR.sub.aC(S)NR.sub.bR.sub.c,
--N(R.sub.a)SOR.sub.b, --N(R.sub.a)SO.sub.2R.sub.b,
--NR.sub.aC(O)OR.sub.b, --NR.sub.aR.sub.b, --NR.sub.aC(O)R.sub.b--,
NR.sub.aC(S)R.sub.b--, --SONR.sub.aR.sub.b--,
--SO.sub.2NR.sub.aR.sub.b--, --OR.sub.a, --OR.sub.aC(O)OR.sub.b--,
--OC(O)NR.sub.aR.sub.b, OC(O)R.sub.a, --OC(O)NR.sub.aR.sub.b--,
--R.sub.aNR.sub.bR.sub.c, --R.sub.aOR.sub.b--, --SR.sub.a,
--SOR.sub.a or --SO.sub.2R.sub.a, wherein R.sub.a, R.sub.b and
R.sub.c are independently selected from hydrogen, C.sub.1-C.sub.8
alkyl, C.sub.3-C.sub.8cycloalkyl, C.sub.5-C.sub.18aryl,
C.sub.5-C.sub.18arylalkyl, C.sub.2-C.sub.18heterocyclyl,
C.sub.2-C.sub.18heteroaryl and C.sub.2-C.sub.18heteroarylalkyl;
R.sub.4 is selected from hydrogen, C.sub.1-C.sub.8alkyl,
C.sub.2-C.sub.8alkynyl, C.sub.3-C.sub.8cycloalkyl,
C.sub.3-C.sub.8cyloalkenyl, C.sub.3-C.sub.8cycloalkylalkyl,
C.sub.5-C.sub.18aryl, C.sub.5-C.sub.18arylalkyl,
C.sub.2-C.sub.18heterocyclyl, C.sub.2-C.sub.18heterocyclylalkyl,
C.sub.2-C.sub.18heteroaryl, C.sub.2-C.sub.18heteroarylalkyl or
C.sub.1-C.sub.8haloalkyl, wherein alkyl, cycloalkyl, cycloalkenyl,
cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl,
heteroaryl and heteroarylalkyl are independently unsubstituted or
substituted with up to three substituents independently selected
from halogen, alkyl, alkenyl, alkynyl, alkoxy, acyl, acyloxy,
amino, hydroxy, keto, nitro, azido, cyano, amide, sulfonamide and
carbamate, wherein the heterocyclyl, heterocyclylalkyl, heteroaryl
and heteroarylalkyl contains up to three heteroatoms selected from
O, N or S; Z is selected from hydrogen, --CH.sub.2OR.sub.5,
--COOR.sub.5, --CONR.sub.5R.sub.6, --NHCOOR.sub.5, --NHCOR.sub.5 or
--NHSO.sub.2R.sub.5, wherein R.sub.5 and R.sub.6 are independently
selected from hydrogen, hydroxyl, C.sub.5-C.sub.18aryl,
C.sub.2-C.sub.18heteroaryl, C.sub.3-C.sub.8cycloalkyl or
C.sub.1-C.sub.8alkyl; wherein R.sub.5 and R.sub.6 are optionally
substituted with one or more substituents selected from fluorine,
chlorine, bromine, iodine, hydroxy, nitro, cyano, azido, nitroso,
oxo (.dbd.O), thioxo (.dbd.S), --SO.sub.2--, amino, hydrazino,
formyl, C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8haloalkylalkoxy,
C.sub.1-C.sub.8haloalkoxy; C.sub.5-C.sub.18arylalkoxy;
C.sub.3-C.sub.8cycloalkyl, C.sub.3-C.sub.8cycloalkyloxy,
C.sub.5-C.sub.18aryl, C.sub.2-C.sub.18heterocyclyl,
C.sub.2-C.sub.18heteroaryl, alkylamino, --COOR.sup.a,
--C(O)R.sup.b, --C(S)R.sup.a, --C(O)NR.sup.aR.sup.b,
--C(S)NR.sup.aR.sup.b, --NR.sup.aC(O)NR.sup.bR.sup.c,
NR.sup.aC(S)NR.sup.bR.sup.c, --N(R.sup.a)SOR.sup.b,
--N(R.sup.a)SO.sub.2R.sup.b, --NR.sup.aC(O)OR.sup.b,
--NR.sup.aR.sup.b, --NR.sup.aC(O)R.sup.b--, NR.sup.aC(S)R.sup.b--,
--SONR.sup.aR.sup.b--, --SO.sub.2NR.sup.aR.sup.b--, --OR.sup.a,
--OR.sup.aC(O)OR.sup.b--, --OC(O)NR.sup.aR.sup.b, OC(O)R.sup.a,
--OC(O)NR.sup.aR.sup.b--, --R.sup.aNR.sup.bR.sup.c,
--R.sup.aOR.sup.b--, --SR.sup.a, --SOR.sup.a or --SO.sub.2R.sup.a,
wherein R.sup.a, R.sup.b and R.sup.c are independently selected
from hydrogen, or optionally substituted groups selected from
alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heteroaryl or
hetroarylalkyl.
3. The compound of Formula (1) as claimed in claim 2, wherein ----
is a single bond or a double bond; X is selected from --O-- or
--N--; n is 0-1; R.sub.1 is selected from hydrogen, methyl, ethyl,
n-propyl, ispopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl,
heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
R.sub.2 and R.sub.3 are independently selected from hydrogen,
fluorine, chlorine, bromine, iodine; hydroxy, nitro, cyano, azido,
nitroso, oxo (.dbd.O), thioxo (.dbd.S), --SO.sub.2--, amino,
hydrazino, formyl, alkyl, haloalkyl group such as trifluoromethyl,
tribromomethyl, trichloromethyl and the like; alkoxy, haloalkoxy
such as --OCH.sub.2C1 and the like; arylalkoxy such as benzyloxy,
phenylethoxy and the like; cycloalkyl, cycloalkyloxy, aryl,
heterocyclyl, heteroaryl, alkylamino, --COOR.sub.a, --C(O)R.sub.b,
--C(S)R.sub.a, --C(O)NR.sub.aR.sub.b, --C(S)NR.sub.aR.sub.b,
--NR.sup.aC(O)NR.sub.bR.sub.c, NR.sub.aC(S)NR.sub.bR.sub.c,
--N(R.sub.a)SOR.sub.b, --N(R.sub.a)SO.sub.2R.sub.b,
--NR.sub.aC(O)OR.sub.b, --NR.sub.aR.sub.b, --NR.sub.aC(O)R.sub.b--,
NR.sub.aC(S)R.sub.b--, --SONR.sub.aR.sub.b--,
--SO.sub.2NR.sub.aR.sub.b--, --OR.sub.a, --OR.sub.aC(O)OR.sub.b--,
--OC(O)NR.sub.aR.sub.b, OC(O)R.sub.a, --OC(O)NR.sub.aR.sub.b--,
--R.sub.aNR.sub.bR.sub.c, --R.sub.aOR.sub.b--, --SR.sub.a,
--SOR.sub.a or --SO.sub.2R.sub.a, wherein R.sub.a, R.sub.b and
R.sub.c are independently selected from hydrogen, alkyl,
cycloalkyl, aryl, arylalkyl, heterocyclyl, heteroaryl and
hetroarylalkyl; R.sub.4 is selected from hydrogen and a substituted
or unsubstituted aryl comprising of phenyl, naphthyl, biphenyl and
indanyl; heteroaryl comprising of pyridinyl, pyridazinyl,
pyrimidyl, triazinyl, pyrrolyl, indolyl, pyrazolyl, imidazolyl,
pyrazinyl, pyrimidinyl, tetrazolyl, furyl, thienyl, thiazolyl,
isoxazolyl, oxazolyl and quinolinyl; cycloalkyl group comprising of
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclooctyl; an
alkyl group comprising of methyl, ethyl, n-propyl, isopropyl,
butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl and octyl;
haloalkyl group comprising of trichloromethyl, trifluoromethyl,
difluoromethyl, trifluoroethyl, trichloroethyl, monofluoromethyl or
monochloromethyl; Z is selected from hydrogen, --CH.sub.2OR.sub.5,
--COOR.sub.5, --CONR.sub.5R.sub.6, --NHCOOR.sub.5, --NHCOR.sub.5,
or --NHSO.sub.2R.sub.5, wherein R.sub.5 and R.sub.6 are selected
from hydrogen or substituted or unsubstituted aryl comprising
phenyl, naphthyl, biphenyl and indanyl: heteroaryl comprising of
pyridinyl, pyridazinyl, pyrimidyl, triazinyl, pyrrolyl, indolyl,
pyrazolyl, imidazolyl, pyrazinyl, pyrimidinyl, tetrazolyl, furyl,
thienyl, thiazolyl, isoxazolyl, oxazolyl and quinolinyl; cycloalkyl
group comprising of cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl and cyclooctyl; an alkyl group comprising of methyl,
ethyl, n-propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl,
hexyl, heptyl and octyl; R.sub.5 and R.sub.6 are optionally
substituted with one or more selected from but not limited to
halogens such as fluorine, chlorine, bromine, iodine; hydroxy,
nitro, cyano, azido, nitroso, oxo (.dbd.O), thioxo (.dbd.S),
--SO.sub.2--, amino, hydrazino, formyl, alkyl, haloalkyl group such
as trifluoromethyl, tribromomethyl, trichloromethyl and the like;
alkoxy, haloalkoxy such as --OCH.sub.2C1 and the like; arylalkoxy
such as benzyloxy, phenylethoxy and the like; cycloalkyl,
cycloalkyloxy, aryl, heterocyclyl, heteroaryl, alkylamino,
--COOR.sup.a, --C(O)R.sup.b, --C(S)R.sup.a, --C(O)NR.sup.aR.sup.b,
--C(S)NR.sup.aR.sup.b, --NR.sup.aC(O)NR.sup.bR.sup.c,
NR.sup.aC(S)NR.sup.bR.sup.c, --N(R.sup.a)SOR.sup.b,
--N(R.sup.a)SO.sub.2R.sup.b, --NR.sup.aC(O)OR.sup.b,
--NR.sup.aR.sup.b, --NR.sup.aC(O)R.sup.b--, NR.sup.aC(S)R.sup.b--,
--SONR.sup.aR.sup.b--, --SO.sub.2NR.sup.aR.sup.b--, --OR.sup.a,
--OR.sup.aC(O)OR.sup.b--, --OC(O)NR.sup.aR.sup.b, OC(O)R.sup.a,
--OC(O)NR.sup.aR.sup.b--, --R.sup.aNR.sup.bR.sup.c,
--R.sup.aOR.sup.b--, --SR.sup.a, --SOR.sup.a or --SO.sub.2R.sup.a,
wherein R.sup.a, R.sup.b and R.sup.c are independently selected
from hydrogen, or optionally substituted groups selected from
alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl,
heteroarylorhetroarylalkyl.
4. The compound of Formula (1) as claimed in claim 1, wherein ----
is a single bond; X is --O--; n is 0-1; R.sub.1 is selected from
C.sub.1-C.sub.8 alkyl or C.sub.3-C.sub.8cycloalkyl; R.sub.2 is
hydrogen; R.sub.3 is selected from halogen, C.sub.1-C.sub.8 alkyl,
C.sub.1-C.sub.8haloalkyl substituted up to 3 halogen selected from
fluoro, chloro, bromo, or iodo, C.sub.1-C.sub.8alkoxy,
C.sub.1-C.sub.8haloalkoxy; C.sub.5-C.sub.18arylalkoxy;
C.sub.3-C.sub.8cycloalkyl, C.sub.3-C.sub.8cycloalkyloxy,
C.sub.5-C.sub.18 aryl, C.sub.2-C.sub.18heterocyclyl or
C.sub.2-C.sub.18heteroaryl; R.sub.4 is selected from hydrogen,
C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.8cycloalkyl,
C.sub.3-C.sub.8cyloalkenyl, C.sub.3-C.sub.8cycloalkylalkyl,
C.sub.5-C.sub.18 aryl, C.sub.5-C.sub.18arylalkyl,
C.sub.2-C.sub.18heterocyclyl, C.sub.2-C.sub.18heterocyclylalkyl,
C.sub.2-C.sub.18heteroaryl, C.sub.2-C.sub.18 heteroarylalkyl or
C.sub.1-C.sub.8haloalkyl, wherein alkyl, cycloalkyl, cycloalkenyl,
cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl,
heteroaryl and heteroarylalkyl are independently unsubstituted or
substituted with up to three substituents independently selected
from halogen, alkyl, alkenyl, alkynyl, alkoxy, acyl, acyloxy,
amino, hydroxy, keto, nitro, azido, cyano, amide, sulfonamide and
carbamate; wherein the heterocyclyl, heterocyclylalkyl, heteroaryl
and heteroarylalkyl contains up to three heteroatoms selected from
O, N or S; Z is selected from the group consisting of hydrogen,
--CH.sub.2OR.sub.5, --COOR.sub.5, --CONR.sub.5R.sub.6,
--NHCOOR.sub.5, --NHCOR.sub.5 or --NHSO.sub.2R.sub.5, wherein
R.sub.5 and R.sub.6 are independently selected from hydrogen,
hydroxyl, C.sub.5-C.sub.18 aryl, C.sub.2-C.sub.18heteroaryl,
C.sub.3-C.sub.8cycloalkyl or C.sub.1-C.sub.8 alkyl; wherein R.sub.5
and R.sub.6 are optionally substituted with one or more
substituents selected fluorine, chlorine, bromine, iodine; hydroxy,
nitro, cyano, azido, nitroso, oxo (.dbd.O), thioxo (.dbd.S),
--SO.sub.2--, amino, hydrazino, formyl, C.sub.1-C.sub.8 alkyl,
C.sub.1-C.sub.8haloalkylalkoxy, C.sub.1-C.sub.8haloalkoxy;
C.sub.5-C.sub.18arylalkoxy; C.sub.3-C.sub.8cycloalkyl,
C.sub.3-C.sub.8cycloalkyloxy, C.sub.6-C.sub.18 aryl,
C.sub.2-C.sub.18heterocyclyl or C.sub.2-C.sub.18heteroaryl.
5. The compound of Formula (1) as claimed in claim 2, wherein ----
is a single bond or a double bond; X is selected from --O-- or
--N--; n is 0-1; R.sub.1 is selected from C.sub.1-C.sub.2 alkyl;
R.sub.2 and R.sub.3 are independently selected from hydrogen,
halogen, C.sub.1-C.sub.8 haloalkyl, C.sub.1-C.sub.8alkoxy, and
C.sub.1-C.sub.8 haloalkoxy; R.sub.4 is selected from hydrogen,
C.sub.1-C.sub.8alkyl, C.sub.3-C.sub.8cycloalkyl,
C.sub.3-C.sub.8cycloalkylalkyl, C.sub.5-C.sub.18aryl,
C.sub.2-C.sub.18heteroaryl, or C.sub.1-C.sub.8haloalkyl, wherein
alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl and
heteroarylalkyl are independently unsubstituted or substituted with
up to three substituents independently selected from halogen,
alkyl, and cyano, wherein the heteroaryl contains up to three
heteroatoms selected from 0 or N; Z is selected from hydrogen,
--CH.sub.2OR.sub.5, --COOR.sub.5, --CONR.sub.5R.sub.6,
--NHCOOR.sub.5, -- or NHCOR.sub.5, wherein R.sub.5 and R.sub.6 are
independently selected from hydrogen, C.sub.5-C.sub.18aryl, or
C.sub.1-C.sub.8alkyl; wherein R.sub.5 and R.sub.6 are optionally
substituted with one or more substituents selected from fluorine,
chlorine, bromine, iodine, hydroxy, and cyano.
6. The compound of Formula (1) as claimed in claim 2, wherein
R.sub.1 is selected from methyl and isopropyl; R.sub.2 is hydrogen;
R.sub.3 is selected from, halogen, C.sub.1-C.sub.2 haloalkyl,
C.sub.1-C.sub.2 alkoxy, and C.sub.1-C.sub.2 haloalkoxy; wherein
haloalkyl and haloalkoxy are substituted with one or more
substituents selected from fluorine and chlorine; R.sub.4 is
selected from hydrogen, C.sub.1-C.sub.2alkyl,
C.sub.3-C.sub.5cycloalkyl, C.sub.3-C.sub.5cycloalkylalkyl,
C.sub.5-C.sub.6 aryl, C.sub.5-C.sub.6heteroaryl, or
C.sub.1-C.sub.2haloalkyl, wherein alkyl, cycloalkylalkyl, aryl,
heteroaryl and heteroarylalkyl are independently unsubstituted or
substituted with up to three substituents independently selected
from halogen, alkyl, and cyano, wherein the heteroaryl contains one
heteroatom as N; Z is selected from hydrogen, --CH.sub.2OR.sub.5,
--COOR.sub.5, --CONR.sub.5R.sub.6, --NHCOOR.sub.5, -- or
NHCOR.sub.5, wherein R.sub.5 and R.sub.6 are independently selected
from hydrogen, C.sub.6 aryl, or C.sub.1-C.sub.3alkyl; wherein
C.sub.6 aryl is substituted with hydroxyl.
7. The compound of Formula (1) as claimed in claim 4, wherein ----
is a single bond; X is --O--; n is 0-1; R.sub.1 is selected from
C.sub.1-C.sub.8 alkyl or C.sub.3-C.sub.8cycloalkyl; R.sub.2 is
hydrogen; R.sub.3 is selected from halogen, C.sub.1-C.sub.8 alkyl,
C.sub.1-C.sub.8haloalkyl substituted up to 3 halogen selected from
fluoro, chloro, bromo, oriodo, C.sub.1-C.sub.8alkoxy,
C.sub.1-C.sub.8haloalkoxy; C.sub.5-C.sub.18arylalkoxy;
C.sub.3-C.sub.8cycloalkyl, C.sub.3-C.sub.8cycloalkyloxy,
C.sub.5-C.sub.18 aryl, C.sub.2-C.sub.18heterocyclyl or
C.sub.2-C.sub.18heteroaryl; R.sub.4 is selected from hydrogen,
C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.8cycloalkyl, C.sub.5-C.sub.18
aryl, C.sub.5-C.sub.18arylalkyl, C.sub.2-C.sub.18heterocyclyl,
C.sub.2-C.sub.18heteroaryl, C.sub.2-C.sub.18heteroarylalkyl or
C.sub.1-C.sub.8haloalkyl, wherein alkyl, cycloalkyl, aryl,
arylalkyl, heterocyclyl, heteroaryl and heteroarylalkyl are
independently unsubstituted or substituted with up to three
substituents independently selected from halogen, alkyl, alkenyl,
alkynyl, alkoxy, acyl, acyloxy, amino, hydroxy, keto, nitro, azido,
cyano, amide, sulfonamide and carbamate; wherein the heterocyclyl,
heteroaryl and heteroarylalkyl contains up to three heteroatoms
selected from O, N or S; Z is selected from the group consisting of
hydrogen, --CH.sub.2OR.sub.5, --COOR.sub.5, --CONR.sub.5R.sub.6,
--NHCOOR.sub.5, --NHCOR.sub.5 or --NHSO.sub.2R.sub.5; R.sub.5 and
R.sub.6 are independently selected from hydrogen, hydroxyl,
C.sub.5-C.sub.18 aryl, C.sub.2-C.sub.18heteroaryl,
C.sub.3-C.sub.8cycloalkyl or C.sub.1-C.sub.8 alkyl; wherein R.sub.5
and R.sub.6 are optionally substituted with one or more
substituents selected from fluorine, chlorine, bromine, iodine;
hydroxy, nitro, cyano, azido, nitroso, oxo (.dbd.O), thioxo
(.dbd.S), --SO.sub.2--, amino, hydrazino, formyl, C.sub.1-C.sub.8
alkyl, C.sub.1-C.sub.8haloalkylalkoxy, C.sub.1-C.sub.8haloalkoxy;
C.sub.5-C.sub.18arylalkoxy; C.sub.3-C.sub.8cycloalkyl,
C.sub.3-C.sub.8cycloalkyloxy, C.sub.6-C.sub.18 aryl,
C.sub.2-C.sub.18heterocyclyl or C.sub.2-C.sub.18heteroaryl.
8. The compound of Formula (1) as claimed in claim 1, wherein ----
is a double bond; X is --N--; n is 0-1; R.sub.1 is selected from
C.sub.1-C.sub.8 alkyl or C.sub.3-C.sub.8 cycloalkyl; R.sub.2 is
hydrogen; R.sub.3 is selected from halogen, C.sub.1-C.sub.8 alkyl,
C.sub.1-C.sub.8haloalkyl substituted up to three halogen selected
from fluoro, chloro, bromo, or iodo, C.sub.1-C.sub.8alkoxy,
C.sub.1-C.sub.8haloalkoxy; C.sub.5-C.sub.18arylalkoxy;
C.sub.3-C.sub.8cycloalkyl, C.sub.3-C.sub.8cycloalkyloxy,
C.sub.5-C.sub.18 aryl, C.sub.2-C.sub.18heterocyclyl or
C.sub.2-C.sub.18heteroaryl; R.sub.4 is selected from hydrogen,
C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.8cycloalkyl,
C.sub.3-C.sub.8cyloalkenyl, C.sub.3-C.sub.8 cycloalkylalkyl,
C.sub.5-C.sub.18 aryl, C.sub.5-C.sub.18arylalkyl,
C.sub.2-C.sub.18heterocyclyl, C.sub.2-C.sub.18heterocyclylalkyl,
C.sub.2-C.sub.18heteroaryl, C.sub.2-C.sub.18heteroarylalkyl or
C.sub.1-C.sub.8haloalkyl; wherein alkyl, cycloalkyl, cycloalkenyl,
cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl,
heteroaryl and heteroarylalkyl are independently unsubstituted or
substituted with up to three substituents independently selected
from halogen, alkyl, alkenyl, alkynyl, alkoxy, acyl, acyloxy,
amino, hydroxy, keto, nitro, azido, cyano, amide, sulfonamide and
carbamate; wherein the heterocyclyl, heterocyclylalkyl, heteroaryl
and heteroarylalkyl contains up to three heteroatoms selected from
O, N or S; Z is selected from the group consisting of hydrogen,
--CH.sub.2OR.sub.5, --COOR.sub.5, --CONR.sub.5R.sub.6,
--NHCOOR.sub.5, --NHCOR.sub.5 or --NHSO.sub.2R.sub.5; R.sub.5 and
R.sub.6 are independently selected from hydrogen, hydroxyl,
C.sub.5-C.sub.18 aryl, C.sub.2-C.sub.18heteroaryl,
C.sub.3-C.sub.8cycloalkyl or C.sub.1-C.sub.8 alkyl; wherein R.sub.5
and R.sub.6 are optionally substituted with, the one or more
substituents are selected from but not limited to halogens such as
fluorine, chlorine, bromine, iodine; hydroxy, nitro, cyano, azido,
nitroso, oxo (.dbd.O), thioxo (.dbd.S), --SO.sub.2--, amino,
hydrazino, formyl, C1-C8 alkyl, C.sub.1-C.sub.8 haloalkylalkoxy,
C.sub.1-C.sub.8 haloalkoxy; C.sub.5-C.sub.18 arylalkoxy;
C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8 cycloalkyloxy,
C.sub.6-C.sub.18 aryl, C.sub.2-C.sub.18 heterocyclyl or
C.sub.2-C.sub.18 heteroaryl.
9. The compound of Formula (1) as claimed in claim 6, wherein ----
is a double bond; X is --N--; n is 0-1; R.sub.1 is selected from
C.sub.1-C.sub.8 alkyl or C.sub.3-C.sub.8 cycloalkyl; R.sub.2 is
hydrogen; R.sub.3 is selected from halogen, C.sub.1-C.sub.8 alkyl,
C.sub.1-C.sub.8 haloalkyl substituted up to 3 halogen selected from
fluoro, chloro, bromo, iodo, C.sub.1-C.sub.8 alkoxy,
C.sub.1-C.sub.8 haloalkoxy; C.sub.5-C.sub.18 arylalkoxy;
C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8 cycloalkyloxy,
C.sub.6-C.sub.18 aryl, C.sub.2-C.sub.18 heterocyclyl or
C.sub.5-C.sub.18 heteroaryl; R.sub.4 is selected from hydrogen,
C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.5-C.sub.18
aryl, C.sub.5-C.sub.18 arylalkyl, C.sub.2-C.sub.18 heterocyclyl,
C.sub.2-C.sub.18 heteroaryl, C.sub.2-C.sub.18 heteroarylalkyl or
C.sub.1-C.sub.8 haloalkyl; wherein alkyl, cycloalkyl, aryl,
arylalkyl, heterocyclyl, heteroaryl and heteroarylalkyl are
independently unsubstituted or substituted with up to three
substituents independently selected from halogen, alkyl, alkenyl,
alkynyl, alkoxy, acyl, acyloxy, amino, hydroxy, keto, nitro, azido,
cyano; wherein the heterocyclyl, heteroaryl and heteroarylalkyl
contains up to three heteroatoms selected from O, N or S; Z is
selected from the group consisting of hydrogen, --CH.sub.2OR.sub.5,
--COOR.sub.5, --CONR.sub.5R.sub.6, --NHCOOR.sub.5, or
--NHCOR.sub.5; wherein R.sub.5 and R.sub.6 are independently
selected from hydrogen, hydroxyl, C6-C18 aryl, C2-C18 heteroaryl,
C3-C8 cycloalkyl or C1-C8 alkyl wherein; R.sub.5 and R.sub.6 are
optionally substituted, with one or more substituents selected from
fluorine, chlorine, bromine, iodine; hydroxy, nitro, cyano, azido,
nitroso, oxo (.dbd.O), thioxo (.dbd.S), --SO.sub.2-amino,
hydrazino, formyl, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8
haloalkylalkoxy, C.sub.1-C.sub.8 haloalkoxy; C.sub.5-C.sub.18
arylalkoxy; C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8
cycloalkyloxy, C.sub.5-C.sub.18 aryl, C.sub.2-C.sub.18 heterocyclyl
or C.sub.2-C.sub.18 heteroaryl.
10. The compound of the Formula (Ia), ##STR00092## wherein X is
selected from --O-- or --N--; n is 0-1; R.sub.1 is selected from
C.sub.1-C.sub.8 alkyl or C.sub.3-C.sub.8 cycloalkyl; R.sub.2 and
R.sub.3 are independently selected from hydrogen, fluoro, chloro,
bromo, iodo, hydroxy, nitro, cyano, azido, nitroso, oxo (.dbd.O),
thioxo (.dbd.S), --SO.sub.2--, amino, hydrazino, formyl,
C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8haloalkyl independently
substituted with up to 3 halogen selected from fluoro, chloro,
bromo, or iodo, C.sub.1-C.sub.8alkoxy, C.sub.1-C.sub.8haloalkoxy;
C.sub.5-C.sub.18arylalkoxy; C.sub.3-C.sub.8cycloalkyl,
C.sub.3-C.sub.8cycloalkyloxy, C.sub.5-C.sub.18 aryl,
C.sub.2-C.sub.18heterocyclyl, C.sub.2-C.sub.18heteroaryl,
alkylamino, --COOR.sub.a, --C(O)R.sub.b, --C(S)R.sub.a,
--C(O)NR.sub.aR.sub.b, --C(S)NR.sub.aR.sub.b,
--NR.sup.aC(O)NR.sub.bR.sub.c, NR.sub.aC(S)NR.sub.bR.sub.c,
--N(R.sub.a)SOR.sub.b, --N(R.sub.a)SO.sub.2R.sub.b,
--NR.sub.aC(O)OR.sub.b, --NR.sub.aR.sub.b, --NR.sub.aC(O)R.sub.b--,
NR.sub.aC(S)R.sub.b--, --SONR.sub.aR.sub.b--,
--SO.sub.2NR.sub.aR.sub.b--, --OR.sub.a, --OR.sub.aC(O)OR.sub.b--,
--OC(O)NR.sub.aR.sub.b, OC(O)R.sub.a, --OC(O)NR.sub.aR.sub.b--,
--R.sub.aNR.sub.bR.sub.c, --R.sub.aOR.sub.b--, --SR.sub.a,
--SOR.sub.a or --SO.sub.2R.sub.a, wherein R.sub.a, R.sub.b and
R.sub.c are independently selected from hydrogen, C.sub.1-C.sub.8
alkyl, C.sub.3-C.sub.8cycloalkyl, C.sub.5-C.sub.18aryl,
C.sub.5-C.sub.18arylalkyl, C.sub.2-C.sub.18heterocyclyl,
C.sub.2-C.sub.18heteroaryl and C.sub.2-C.sub.18hetroarylalkyl.
R.sub.4 is selected from hydrogen, C.sub.1-C.sub.8 alkyl,
C.sub.3-C.sub.8cycloalkyl, C.sub.6-C.sub.18aryl or
C.sub.2-C.sub.18heteroaryl; wherein alkyl, cycloalkyl, aryl, and
heteroaryl are independently unsubstituted or substituted with up
to three substituents independently selected from halogen, alkyl,
alkenyl, alkynyl, alkoxy, acyl, acyloxy, amino, hydroxy, keto,
nitro, azido, cyano; wherein the heteroaryl contains up to three
heteroatoms selected from O, N or S; Z is selected from
--CH.sub.2OR.sub.5, --COOR.sub.5, --CONR.sub.5R.sub.6, or
--CONHR.sub.7, R.sub.5 and R.sub.6 are independently selected from
hydrogen, hydroxyl, C.sub.5-C.sub.18 aryl,
C.sub.2-C.sub.18heteroaryl, C.sub.3-C.sub.8cycloalkyl or
C.sub.1-C.sub.8 alkyl; wherein R.sub.5 and R.sub.6 are optionally
substituted, with one or more substituents selected from fluorine,
chlorine, bromine, iodine; hydroxy, nitro, cyano, azido, nitroso,
oxo (.dbd.O), thioxo (.dbd.S), --SO.sub.2--, amino, hydrazino,
formyl, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 haloalkylalkoxy,
C.sub.1-C.sub.8 haloalkoxy; C.sub.5-C.sub.18 arylalkoxy;
C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8 cycloalkyloxy,
C.sub.5-C.sub.18 aryl, C.sub.2-C.sub.18 heterocyclyl,
C.sub.2-C.sub.18 heteroaryl, alkylamino, --COOR.sup.a,
--C(O)R.sup.b, --C(S)R.sup.a, --C(O)NR.sup.aR.sup.b,
--C(S)NR.sup.aR.sup.b, --NR.sup.aC(O)NR.sup.bR.sup.c,
NR.sup.aC(S)NR.sup.bR.sup.c, --N(R.sup.a)SOR.sup.b,
--N(R.sup.a)SO.sub.2R.sup.b, --NR.sup.aC(O)OR.sup.b,
--NR.sup.aR.sup.b, --NR.sup.aC(O)R.sup.b--, NR.sup.aC(S)R.sup.b--,
--SONR.sup.aR.sup.b--, --SO.sub.2NR.sup.aR.sup.b--, --OR.sup.a,
--OR.sup.aC(O)OR.sup.b--, --OC(O)NR.sup.aR.sup.b, OC(O)R.sup.a,
--OC(O)N--R.sup.aR.sup.b--, --R.sup.aNR.sup.bR.sup.c,
--R.sup.aOR.sup.b--, SR.sup.a, --SOR.sup.a or --SO.sub.2R.sup.a,
wherein R.sup.a, R.sup.b and R.sup.c are independently selected
from hydrogen, or optionally substituted groups selected from
alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl,
heteroarylorhetroarylalkyl. R.sub.7 represents --OR.sub.8, ortho
substituted aniline, amino aryl and amino heteroaryl, which may be
further substituted, wherein R.sub.8 is selected from hydrogen,
optionally substituted groups selected from alkyl, aryl,
heterocyclyl and --COR.sub.9, wherein R.sub.9 is selected from
alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl.
11. The compound of formula (I) or (Ia) as claimed in claim 1, or
its stereoisomers, pharmaceutically acceptable salts, complexes,
hydrates, solvates, tautomers, polymorphs, racemic mixtures,
optically active forms and pharmaceutically active derivative
thereof, which is selected from a group consisting of: .+-.Ethyl
2-(-7-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-2,3,5,7-tetrahydrobenzo[5-
,6]oxepino[4,3-c]pyridin-5-yl)acetate Ethyl
2-((5S,7R)-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-2,3,5,7-tetrahydrobe-
nzo[5,6]oxepino[4,3-c]pyridin-5-yl)acetate Ethyl
2-((5S,7S)-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-2,3,5,7-tetrahydrobe-
nzo[5,6]oxepino[4,3-c]pyridin-5-yl)acetate Ethyl
2-((5R,7S)-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-2,3,5,7-tetrahydrobe-
nzo[5,6]oxepino[4,3-c]pyridin-5-yl)acetate Ethyl
2-((5R,7R)-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-2,3,5,7-tetrahydrobe-
nzo[5,6]oxepino[4,3-c]pyridin-5-yl)acetate .+-.Ethyl
2-(7-cyclohexyl-9-methoxy-2-methyl-3-oxo-2,3,5,7-tetrahydrobenzo[5,6]oxep-
ino[4,3-c]pyridin-5-yl)acetate .+-.Ethyl
2-(7-(cyclopropylmethyl)-9-methoxy-2-methyl-3-oxo-2,3,5,7-tetrahydrobenzo-
[5,6]oxepino[4,3-c]pyridin-5-yl)acetate .+-.Ethyl
2-(9-methoxy-2-methyl-7-(5-methylpyridin-2-yl)-3-oxo-2,3,5,7-tetrahydrobe-
nzo[5,6]oxepino[4,3-c]pyridin-5-yl)acetate .+-.Ethyl
2-(7-(4-chlorophenyl)-9-fluoro-2-methyl-3-oxo-2,3,5,7-tetrahydrobenzo[5,6-
]oxepino[4,3-c]pyridin-5-yl)acetate .+-.Ethyl
2-(7-(4-chlorophenyl)-2-methyl-3-oxo-9-(trifluoromethyl)-2,3,5,7-tetrahyd-
robenzo[5,6]oxepino[4,3-c]pyridin-5-yl)acetate
.+-.7-(4-chlorophenyl)-5-(2-hydroxyethyl)-9-methoxy-2-methyl-5,7-dihydrob-
enzo[5,6]oxepino[4,3-c]pyridin-3(2H)-one
.+-.2-(-7-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-2,3,5,7-tetrahydroben-
zo[5,6]oxepino[4,3-c]pyridin-5-yl)-N-ethylacetamide
.+-.2-((5S,7R)-7-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-2,3,5,7-tetrah-
ydrobenzo[5,6]oxepino[4,3-c]pyridin-5-yl)-N-ethylacetamide
.+-.2-((5S,7S)-7-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-2,3,5,7-tetrah-
ydrobenzo[5,6]oxepino[4,3-c]pyridin-5-yl)-N-ethylacetamide
2-((5S,7R)-7-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-2,3,5,7-tetrahydro-
benzo[5,6]oxepino[4,3-c]pyridin-5-yl)-N-ethylacetamide
2-((5S,7S)-7-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-2,3,5,7-tetrahydro-
benzo[5,6]oxepino[4,3-c]pyridin-5-yl)-N-ethylacetamide
2-((5R,7S)-7-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-2,3,5,7-tetrahydro-
benzo[5,6]oxepino[4,3-c]pyridin-5-yl)-N-ethylacetamide
2-((5R,7R)-7-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-2,3,5,7-tetrahydro-
benzo[5,6]oxepino[4,3-c]pyridin-5-yl)-N-ethylacetamide
.+-.2-(7-cyclohexyl-9-methoxy-2-methyl-3-oxo-2,3,5,7-tetrahydrobenzo[5,6]-
oxepino[4,3-c]pyridin-5-yl)-N-ethylacetamide
.+-.2-((5S,7R)-7-cyclohexyl-9-methoxy-2-methyl-3-oxo-2,3,5,7-tetrahydrobe-
nzo[5,6]oxepino[4,3-c]pyridin-5-yl)-N-ethylacetamide
.+-.2-((5S,7S)-7-cyclohexyl-9-methoxy-2-methyl-3-oxo-2,3,5,7-tetrahydrobe-
nzo[5,6]oxepino[4,3-c]pyridin-5-yl)-N-ethylacetamide
.+-.2-(7-(cyclopropylmethyl)-9-methoxy-2-methyl-3-oxo-2,3,5,7-tetrahydrob-
enzo[5,6]oxepino[4,3-c]pyridin-5-yl)-N-ethylacetamide
.+-.2-((5S,7R)-7-(cyclopropylmethyl)-9-methoxy-2-methyl-3-oxo-2,3,5,7-tet-
rahydrobenzo[5,6]oxepino[4,3-c]pyridin-5-yl)-N-ethylacetamide
.+-.2-((5S,7S)-7-(cyclopropylmethyl)-9-methoxy-2-methyl-3-oxo-2,3,5,7-tet-
rahydrobenzo[5,6]oxepino[4,3-c]pyridin-5-yl)-N-ethylacetamide
.+-.2-(9-methoxy-2-methyl-7-(5-methylpyridin-2-yl)-3-oxo-2,3,5,7-tetrahyd-
robenzo[5,6]oxepino[4,3-c]pyridin-5-yl)-N-ethylacetamide
.+-.2-((5S,7S)-9-methoxy-2-methyl-7-(5-methylpyridin-2-yl)-3-oxo-2,3,5,7--
tetrahydrobenzo[5,6]oxepino[4,3-c]pyridin-5-yl)-N-ethylacetamide
.+-.2-((5S,7R)-9-methoxy-2-methyl-7-(5-methylpyridin-2-yl)-3-oxo-2,3,5,7--
tetrahydrobenzo[5,6]oxepino[4,3-c]pyridin-5-yl)-N-ethylacetamide
.+-.2-(7-(4-chlorophenyl)-9-fluoro-2-methyl-3-oxo-2,3,5,7-tetrahydrobenzo-
[5,6]oxepino[4,3-c]pyridin-5-yl)-N-ethylacetamide
.+-.2-((5S,7R)-9-fluoro-2-methyl-3-oxo-7-phenyl-2,3,5,7-tetrahydrobenzo[5-
,6]oxepino[4,3-c]pyridin-5-yl)-N-ethylacetamide
.+-.2-((5S,7S)-9-fluoro-2-methyl-3-oxo-7-phenyl-2,3,5,7-tetrahydrobenzo[5-
,6]oxepino[4,3-c]pyridin-5-yl)-N-ethylacetamide
.+-.2-(7-(4-chlorophenyl)-2-methyl-3-oxo-9-(trifluoromethyl)-2,3,5,7-tetr-
ahydrobenzo[5,6]oxepino[4,3-c]pyridin-5-yl)-N-ethylacetamide
.+-.2-((5S,7R)-2-methyl-3-oxo-7-phenyl-9-(trifluoromethyl)-2,3,5,7-tetrah-
ydrobenzo[5,6]oxepino[4,3-c]pyridin-5-yl)-N-ethylacetamide
.+-.2-((5S,7S)-2-methyl-3-oxo-7-phenyl-9-(trifluoromethyl)-2,3,5,7-tetrah-
ydrobenzo[5,6]oxepino[4,3-c]pyridin-5-yl)-N-ethylacetamide
.+-.Ethyl
2-(7-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c]pyr-
ido[3,4-e]azepin-5-yl)acetate .+-.Ethyl
2-(7-cyclohexyl-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c]pyrido[3,-
4-e]azepin-5-yl)acetate .+-.Ethyl
2-(9-methoxy-2-methyl-3-oxo-7-(pyridin-2-yl)-3,5-dihydro-2H-benzo[c]pyrid-
o[3,4-e]azepin-5-yl)acetate .+-.Ethyl
2-(7-(cyclopropylmethyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c]-
pyrido[3,4-e]azepin-5-yl)acetate .+-.Ethyl
2-(9-methoxy-2-methyl-3-oxo-7-(trifluoromethyl)-3,5-dihydro-2H-benzo[c]py-
rido[3,4-e]azepin-5-yl)acetate .+-.Ethyl
2-(9-methoxy-2,7-dimethyl-3-oxo-3,5-dihydro-2H-benzo[c]pyrido[3,4-e]azepi-
n-5-yl)acetate .+-.Ethyl
2-(9-methoxy-2-methyl-7-(5-methylpyridin-2-yl)-3-oxo-3,5-dihydro-2H-benzo-
[c]pyrido[3,4-e]azepin-5-yl)acetate .+-.Ethyl
2-(7-(4-chlorophenyl)-2-isopropyl-9-methoxy-3-oxo-3,5-dihydro-2H-benzo[c]-
pyrido[3,4-e]azepin-5-yl)acetate .+-.Ethyl
2-(7-(4-chlorophenyl)-9-fluoro-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c]pyri-
do[3,4-e]azepin-5-yl)acetate .+-.Ethyl
2-(7-(2,6-difluorophenyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c-
]pyrido[3,4-e]azepin-5-yl)acetate .+-.Ethyl
2-(7-(4-chloro-2-methylphenyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-be-
nzo[c]pyrido[3,4-e]azepin-5-yl)acetate
.+-.2-(7-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c-
]pyrido[3,4-e]azepin-5-yl)-N-ethylacetamide
(S)-2-(7-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c-
]pyrido[3,4-e]azepin-5-yl)-N-ethylacetamide.
(R)-2-(7-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c-
]pyrido[3,4-e]azepin-5-yl)-N-ethylacetamide.
.+-.2-(7-cyclohexyl-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c]pyrid-
o[3,4-e]azepin-5-yl)-N-ethylacetamide
(S)-2-(7-cyclohexyl-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c]pyrid-
o[3,4-e]azepin-5-yl)-N-ethylacetamide
(R)-2-(7-cyclohexyl-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c]pyrid-
o[3,4-e]azepin-5-yl)-N-ethylacetamide
.+-.2-(9-methoxy-2-methyl-3-oxo-7-(pyridin-2-yl)-3,5-dihydro-2H-benzo[c]p-
yrido[3,4-e]azepin-5-yl)-N-ethylacetamide
(S)-2-(9-methoxy-2-methyl-3-oxo-7-(pyridin-2-yl)-3,5-dihydro-2H-benzo[c]p-
yrido[3,4-e]azepin-5-yl)-N-ethylacetamide
(R)-2-(9-methoxy-2-methyl-3-oxo-7-(pyridin-2-yl)-3,5-dihydro-2H-benzo[c]p-
yrido[3,4-e]azepin-5-yl)-N-ethylacetamide
.+-.2-(7-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c-
]pyrido[3,4-e]azepin-5-yl)acetamide
.+-.2-(7-(4-chlorophenyl)-9-hydroxy-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c-
]pyrido[3,4-e]azepin-5-yl)-N-ethylacetamide
.+-.2-(7-(cyclopropylmethyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-benz-
o[c]pyrido[3,4-e]azepin-5-yl)-N-ethylacetamide
(S)-2-(7-(cyclopropylmethyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-benz-
o[c]pyrido[3,4-e]azepin-5-yl)-N-ethylacetamide
(R)-2-(7-(cyclopropylmethyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-benz-
o[c]pyrido[3,4-e]azepin-5-yl)-N-ethylacetamide
.+-.2-(7-(4-chlorophenyl)-9-(difluoromethoxy)-2-methyl-3-oxo-3,5-dihydro--
2H-benzo[c]pyrido[3,4-e]azepin-5-yl)-N-ethylacetamide
.+-.2-(9-methoxy-2-methyl-3-oxo-7-(trifluoromethyl)-3,5-dihydro-2H-benzo[-
c]pyrido[3,4-e]azepin-5-yl)-N-ethylacetamide
(S)-2-(9-methoxy-2-methyl-3-oxo-7-(trifluoromethyl)-3,5-dihydro-2H-benzo[-
c]pyrido[3,4-e]azepin-5-yl)-N-ethylacetamide
(R)-2-(9-methoxy-2-methyl-3-oxo-7-(trifluoromethyl)-3,5-dihydro-2H-benzo[-
c]pyrido[3,4-e]azepin-5-yl)-N-ethylacetamide
.+-.2-(7-(4-cyanophenyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c]-
pyrido[3,4-e]azepin-5-yl)-N-ethylacetamide
.+-.2-(9-methoxy-2-methyl-7-(5-methylpyridin-2-yl)-3-oxo-3,5-dihydro-2H-b-
enzo[c]pyrido[3,4-e]azepin-5-yl)-N-ethylacetamide
.+-.2-(7-(4-chlorophenyl)-2-methyl-3-oxo-9-(trifluoromethyl)-3,5-dihydro--
2H-benzo[c]pyrido[3,4-e]azepin-5-yl)-N-ethylacetamide
.+-.2-(7-(4-chlorophenyl)-2-isopropyl-9-methoxy-3-oxo-3,5-dihydro-2H-benz-
o[c]pyrido[3,4-e]azepin-5-yl)-N-ethylacetamide
.+-.2-(7-(4-chlorophenyl)-9-fluoro-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c]-
pyrido[3,4-e]azepin-5-yl)-N-ethylacetamide
.+-.2-(7-(2,6-difluorophenyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-ben-
zo[c]pyrido[3,4-e]azepin-5-yl)-N-ethylacetamide .+-.2-(7-(4-chloro,
2-methylphenyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c]pyrido[3,-
4-e]azepin-5-yl)-N-ethylacetamide
.+-.2-(7-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c-
]pyrido[3,4-e]azepin-5-yl)-N-(4-hydroxyphenyl)acetamide
(S)-2-(7-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c-
]pyrido[3,4-e]azepin-5-yl)-N-(4-hydroxyphenyl)acetamide
(R)-2-(7-(4-chlorophenyl)-9-methoxy
-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c]pyrido[3,4-e]azepin-5-yl)-N-(4-hyd-
roxyphenyl)acetamide
.+-.7-(4-chlorophenyl)-9-methoxy-2,5-dimethyl-2H-benzo[c]pyrido[3,4-e]aze-
pin-3(5H)-one
(S)-7-(4-chlorophenyl)-9-methoxy-2,5-dimethyl-2H-benzo[c]pyrido[3,4-e]aze-
pin-3(5H)-one
(R)-7-(4-chlorophenyl)-9-methoxy-2,5-dimethyl-2H-benzo[c]pyrido[3,4-e]aze-
pin-3(5H)-one
.+-.7-(4-chlorophenyl)-9-methoxy-2-methyl-2H-benzo[c]pyrido[3,4-e]azepin--
3(5H)-one
.+-.2-(7-(4-chlorophenyl)-2-methyl-3-oxo-9-(trifluoromethyl)-3,5-
-dihydro-2H-benzo[c]pyrido[3,4-e]azepin-5-yl)acetic acid
.+-.2-(7-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c-
]pyrido[3,4d]azepin-5-yl)acetic acid .+-.tert-butyl
((7-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-enzo[c]pyrid-
o[3,4-e]azepin-5-yl)methyl)carbamate and
.+-.N-((7-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-benzo[-
c]pyrido[3,4-e]azepin-5-yl)methyl)acetamide.
12. A process of preparation of the compound of Formula (I) as
claimed in claim 1, or its tautomers, polymorphs, stereoisomers,
prodrugs, solvate, co-crystals or pharmaceutically acceptable salts
thereof.
13. A pharmaceutical composition comprising a compound of formula
(I) or a pharmaceutically acceptable salt thereof of as claimed in
claim 1, together with a pharmaceutically acceptable carrier,
optionally in combination with one or more other pharmaceutical
compositions.
14. The pharmaceutical composition according to claim 13, wherein
the composition is in the form of a tablet, capsule, powder, syrup,
solution, aerosol or suspension.
15. A compound according to claim 1, or a pharmaceutically
acceptable salt thereof for use in the manufacture of a medicament
for the inhibiting one or more BET family bromodomains in a
cell.
16. A method of inhibiting one or more BET family bromodomains in a
cell comprising treating said cell with an effective amount of the
compound according to claim 1.
17. A method of treating a condition mediated by one or more BET
family bromodomains, comprising administering to a subject
suffering from a condition mediated by one or more BET family
bromodomains a therapeutically effective amount of the compound
according to claim 1.
18. A method for the treatment and/or prevention of a proliferative
disorder or cancer, comprising administering to a subject suffering
from the proliferative disorder or cancer a therapeutically
effective amount of the compound according to claim 1.
19. The method as claimed in claim 18, wherein said compound or
composition is administered in combination with at least one
compound selected from cytotoxic agents or non-cytotoxic agents to
a mammal in need thereof.
20. (canceled)
21. A method for the treatment and/or prevention of a condition
mediated by one or more BET family bromodomains or a proliferative
disorder or cancer, comprising administering to a subject suffering
from the condition mediated by one or more BET family bromodomains
or the proliferative disorder or cancer a therapeutically effective
amount of the compound according to claim 1.
22. A method for the treatment of cancer, said method comprising
administering a combination of the compound according to claim 1
with other clinically relevant cytotoxic agents or non-cytotoxic
agents to a mammal in need thereof.
23. A method of treatment of cancer, said method comprising
administering a combination of the compound according to claim 1
with other clinically relevant immune modulators agents to a mammal
in need of thereof.
Description
TECHNICAL FIELD
[0001] The present disclosure relates to the field of medicinal
chemistry and more particularly to the development of compounds as
inhibitors of one or more BET family of bromodomians. The present
disclosure relates to heterocyclic compounds of the Formula (I),
its stereoisomers, pharmaceutically acceptable salts, complexes,
hydrates, solvates, tautomers, polymorphs, racemic mixtures,
optically active forms and pharmaceutically active derivative
thereof and pharmaceutical compositions containing them as the
active ingredient.
##STR00002##
[0002] The present disclosure further relates to the synthesis and
characterization of aforementioned compounds to exhibit anticancer
activity. The compounds of the present disclosure are useful as
medicaments and their use in the manufacture of medicaments for
treatment, prevention or suppression of diseases, and conditions
mediated by one or more BET family of bromodomains.
BACKGROUND
[0003] Transcriptional regulation is a major event in cell
differentiation, proliferation and apoptosis. Transcriptional
activation of a set of genes determines cellular function and is
tightly regulated by a variety of factors. One of the regulatory
mechanisms involved in this process is an alteration in the
tertiary structure of DNA, which affects transcription factors to
their target DNA regiments. Nucleosomal integrity is regulated by
the acetylation status of the core histone, with the result being
permissiveness to transcription. The regulations of transcription
factor are thought to involve changes in the structure of
chromatin. Changing the affinity of histone proteins for coiled DNA
in the nucleosome alters the structure of chromatin. Hypoacetylated
histones are believed to have greater affinity to the DNA and form
a tightly bound DNA-histone complex and render the DNA inaccessible
to transcriptional regulation. The acetylating status of the
histone is governed by the balanced activities of the histone
acetyl transferase (HAT) and histone deacetylase (HDAC). The
bromodomain and extraterminal family of proteins called as BET
proteins are readers of the acetyl status of histone and changes
the chromatin structure and gene expression.
[0004] The BET family of bromodomain containing proteins comprises
four proteins, namely BRD2, BRD3, BRD4 and BRDT, which are widely
expressed in various tissues, except BRDT which is localized in the
testes. Each of the BRD proteins contains tandem bromodomains
capable of binding to acetylated lysine residues in histones H3 and
H4. It has been reported that BRD2 and BRD3 are associated with
histones along actively transcribed genes and involved in
facilitating transcriptional elongation (Leroy et al, Mol. Cell.
2008 30(1):51-60), while BRD4 appears to be involved in the
recruitment of the pTEF-[beta] complex to nuclesomes, which results
in phosphorylation of RNA polymerase II and increases the
transcriptional elongation of neighboring genes. (Hargreaves et al,
Cell, 2009 138(1): 129-145).
[0005] BRD4 or BRD3 may fuse with NUT (nuclear protein in testis)
forming novel fusion oncogenes, BRD4-NUT or BRD3-NUT, in a highly
malignant form of epithelial neoplasia (French et al. Cancer
Research, 2003, 63, 304-307 and French et al. Journal of Clinical
Oncology, 2004, 22 (20), 4135-4139). Data suggests that BRD-NUT
fusion proteins contribute to carcinogenesis (Oncogene, 2008, 27,
2237-2242). A BET protein which includes BRD4 have been shown to be
important regulators of gene expression profiles in numerous
diseases such as cancer, diabetes, obesity, cardiovascular and
renal disorders. Currently several BRD4 inhibitors is in various
stages of clinical trial for cancer such as IBET-762, JQ1, OTX-015
and RVX-2135 (P. Filippakopoulos, et. al., Nature Review Drug
Discovery, 13, 2014, 337-356, M. Brand, et. al., ACS Chem. Biol,
10, 2015, 22-39).
##STR00003##
[0006] A tricyclic aryl compound as squalene synthase inhibitors
has been disclosed in WO2008133288 for the treatment of
hypercholesterolemia, hypertriglyceridemia and hypo-HDL
cholesterolemia and/or arteriosclerosis.
##STR00004##
[0007] Masanori Ichikawa et. al published a paper (ACS Med. Chem.
Lett., 2013, 932-936) describing the squalene synthase inhibitors
DF4611 (B) and also Nils Griebenow, et. al. published a paper
(Bioorg. Med. Chem. Lett. 21, 2011, 3648-3653) on the synthesis of
novel 4H,6H-[2]benzoxepino[4,5-c][1,2]oxazoles (C) as squalene
synthase inhibitors.
##STR00005##
[0008] Although, there are several chemotherapies and target
therapies based drugs for cancer, an effective cure for cancer
still remains elusive. Further, development of acquired resistance
and disease relapse are major issues that still need to be
addressed. Even though several bromodomain inhibitors are known in
the clinic as well as in the preclinic, still remains a need for
finding potent bromodomain inhibitors having desirable drug like
properties.
[0009] Therefore, the present invention provides novel and drug
like molecules having good potency as BRD4 inhibitors which can
inhibit the binding of acetylated lysine residue of histone for
controlling gene expressions in various diseases.
SUMMARY
[0010] The present disclosure is based on the development of
compounds of Formula I (see below) exhibiting advantageous
anti-cancer properties. Thus, the present disclosure provides a
compound of Formula I
##STR00006##
[0011] or its stereoisomers, pharmaceutically acceptable salts,
complexes, hydrates, solvates, tautomers, polymorphs, racemic
mixtures, optically active forms and pharmaceutically active
derivative thereof,
wherein -------- is a single bond or a double bond; X is selected
from --O-- or --N--; n is 0-6; R.sub.1 is selected from alkyl or
cycloalkyl; R.sub.2 and R.sub.3 are independently selected from
hydrogen, halogen, hydroxy, nitro, cyano, azido, nitroso, oxo
(.dbd.O), thioxo (.dbd.S), --SO.sub.2--, amino, hydrazino, formyl,
alkyl, haloalkyl, alkoxy, haloalkoxy; arylalkoxy; cycloalkyl,
cycloalkyloxy, aryl, heterocyclyl, heteroaryl, alkylamino,
--COOR.sub.a, --C(O)R.sub.b, --C(S)R.sub.a, --C(O)NR.sub.aR.sub.b,
--C(S)NR.sub.aR.sub.b, --NR.sup.aC(O)NR.sub.bR.sub.c,
NR.sub.aC(S)NR.sub.bR.sub.c, --N(R.sub.a)SOR.sub.b,
--N(R.sub.a)SO.sub.2R.sub.b, --NR.sub.aC(O)OR.sub.b,
--NR.sub.aR.sub.b, --NR.sub.aC(O)R.sub.b--, NR.sub.aC(S)R.sub.b--,
--SONR.sub.aR.sub.b--, --SO.sub.2NR.sub.aR.sub.b--, --OR.sub.a,
--OR.sub.aC(O)OR.sub.b--, --OC(O)NR.sub.aR.sub.b, OC(O)R.sub.a,
OC(O)NR.sub.aR.sub.b--, --R.sub.aNR.sub.bR.sub.c,
--R.sub.aOR.sub.b--, --SR.sub.a, --SOR.sub.a or --SO.sub.2R.sub.a,
wherein R.sub.a, R.sub.b and R.sup.c are independently selected
from hydrogenalkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl,
heteroarylorhetroarylalkyl; R.sub.4 is selected from hydrogen,
alkyl, cycloalkyl, cyloalkenyl, cycloalkylalkyl, aryl, arylalkyl,
heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl or
haloalkyl; Z is selected from hydrogen, --CH.sub.2OR.sub.5,
--COOR.sub.5, --CONR.sub.5R.sub.6, --NHCOOR.sub.5, --NHCOR.sub.5 or
--NHSO.sub.2R.sub.5; and R.sub.5 and R.sub.6 are independently
selected from hydrogen, hydroxyl, aryl, heteroaryl, cycloalkyl or
alkyl.
[0012] The present disclosure relates to a composition comprising a
compound of Formula (I) or its stereoisomers, pharmaceutically
acceptable salts, complexes, hydrates, solvates, tautomers,
polymorphs, racemic mixtures, optically active forms and
pharmaceutically active derivative thereof together with a
carrier.
[0013] The present disclosure relates to a pharmaceutical
composition comprising a compound of Formula I or its
stereoisomers, pharmaceutically acceptable salts, complexes,
hydrates, solvates, tautomers, polymorphs, racemic mixtures,
optically active forms and pharmaceutically active derivative
thereof, together with a pharmaceutically acceptable carrier,
optionally in combination with one or more other pharmaceutical
compositions.
[0014] The present disclosure further relates to a method of
preventing or treating proliferative diseases by administering a
therapeutic effective amount of novel compound of the Formula (I)
or a pharmaceutically acceptable salt and/or prodrug.
[0015] The present disclosure relates to a process of preparation
of compound of Formula (I) or its stereoisomers, pharmaceutically
acceptable salts, complexes, hydrates, solvates, tautomers,
polymorphs, racemic mixtures, optically active forms and
pharmaceutically active derivative thereof.
[0016] These and other features, aspects, and advantages of the
present subject matter will become better understood with reference
to the following description. This summary is provided to introduce
a selection of concepts in a simplified form. This summary is not
intended to identify key features or essential features of the
disclosure, nor is it intended to be used to limit the scope of the
subject matter.
DETAILED DESCRIPTION
[0017] Those skilled in the art will be aware that the present
disclosure is subject to variations and modifications other than
those specifically described. It is to be understood that the
present disclosure includes all such variations and modifications.
The disclosure also includes all such steps, features, compositions
and compounds referred to or indicated in this specification,
individually or collectively, and any and all combinations of any
or more of such steps or features.
Definitions
[0018] For convenience, before further description of the present
disclosure, certain terms employed in the specification, and
examples are collected here. These definitions should be read in
the light of the remainder of the disclosure and understood as by a
person of skill in the art. The terms used herein have the meanings
recognized and known to those of skill in the art, however, for
convenience and completeness, particular terms and their meanings
are set forth below.
[0019] The articles "a", "an" and "the" are used to refer to one or
to more than one (i.e., to at least one) of the grammatical object
of the article.
[0020] The terms "comprise" and "comprising" are used in the
inclusive, open sense, meaning that additional elements may be
included. Throughout this specification, unless the context
requires otherwise the word "comprise", and variations, such as
"comprises" and "comprising", will be understood to imply the
inclusion of a stated element or step or group of element or steps
but not the exclusion of any other element or step or group of
element or steps.
[0021] The term "including" is used to mean "including but not
limited to". "Including" and "including but not limited to" are
used interchangeably.
[0022] In the structural formulae given herein and throughout the
present disclosure, the following terms have been indicated
meaning, unless specifically stated otherwise.
[0023] The term "alkyl" refers to straight or branched aliphatic
hydrocarbon chain having the 1-8 carbon atoms. This term is
exemplified by groups such as n-butyl, iso-butyl, t-butyl, n-hexyl
and the like. The groups may be optionally substituted.
[0024] The term "aryl" refers to aromatic radicals having 5 to 18
carbon atoms having a single ring (e.g. phenyl) or multiple rings
(e.g. biphenyl), or multiple condensed (fused) rings (e.g. naphthyl
or anthranyl), which may be optionally substituted by one or more
substituents. Preferred aryl groups, without limitation, include
phenyl, naphthyl, indanyl, biphenyl and the like.
[0025] The term "arylalkyl" refers to an aryl group directly bonded
to an alkyl group, which may be optionally substituted by one or
more substituents. Preferred arylalkyl groups, without limitation,
include --CH.sub.2C.sub.6H.sub.5, --C.sub.2H.sub.4C.sub.6H.sub.5
and the like.
[0026] The term "heterocyclyl" refers to a heterocyclic ring
radical which may be optionally substituted by one or more
substituents. The heterocyclyl ring radical may be attached to the
main structure at any heteroatom or carbon atom that results in the
creation of a stable structure.
[0027] Furthermore the term "heterocyclyl" refers to a stable 2 to
18 membered rings radical, which consists of carbon atoms and from
one to five heteroatom's selected from nitrogen, phosphorus, oxygen
and sulfur. For purposes of this invention the heterocyclic ring
radical may be monocyclic, bicyclic or tricyclic ring systems, and
the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the
heterocyclic ring radical may be optionally oxidized to various
oxidation states. In addition, the nitrogen atom may be optionally
quaternized; and the ring radical may be partially or fully
saturated. Preferred heterocyclyl groups, without limitation,
include azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl,
benzofuranyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl,
naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl,
phenoxazinyl, phthalazinyl, pyrazolyl, pyridyl, pteridinyl,
purinyl, quinazolinyl, qunioxalinyl, quinolinyl, isoquinolinyl,
tetrazolyl, imidazolyl, tetrahydroisoquinolinyl, piperidinyl,
piperazinyl, homopiperazinyl, 2-oxoazepinyl, azepinyl, pyrrolyl,
4-piperidonyl, pyrrolidinyl, pyrazinyl, pyrimidinyl, pyridazinyl,
oxazolyl, oxazolinyl, triazolyl, indanyl, isoxazolyl,
isoxazolidinyl, thiazolyl, thiazolinyl, thiazolidinyl,
isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl,
indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl,
quinolyl, isoquinolyl, decahydroisoquinolyl, benzimidazolyl,
thiadiazolyl, benzopyranyl, benzothiazolyl, benzooxazolyl, thienyl,
morpholinyl, thiomorpholinyl, thiamorpholinyl sulfoxide, furyl,
tetrahydrofuryl, tetrahydropyranyl, chromanyl and isochromanyl.
[0028] The term "heteroaryl" refers to a heteroaromatic carbocyclic
group of 2 to 18 carbon atoms having a single ring (e.g. pyridine)
or multiple rings (e.g. isoquinoline), or multiple condensed
(fused) rings. Preferred heteroaryls include thiophene, pyrazole,
thiazole, pyridine and the like. The groups may be optionally
substituted.
[0029] The term "heteroarylalkyl" refers to a heteroaryl group
directly bonded to an alkyl group, which may be optionally
substituted by one or more substituents. Preferred heteroarylalkyl
groups, without limitation, include-CH.sub.2-pyridinyl,
--C.sub.2H.sub.4-- furyl and the like.
[0030] The term "cycloalkyl" refers to non-aromatic mono or
polycyclic ring system of about 3 to 12 carbon atoms, which may be
optionally substituted by one or more substituent's. The polycyclic
ring denotes hydrocarbon systems containing two or more ring
systems with one or more ring carbon atoms in common, i.e., a
spiro, fused or bridged structures. Preferred cycloalkyl groups
include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cyclooctanyl, perhydronaphthyl, adamantyl, noradamantyl
and norbornyl groups, bridged cyclic groups or spirobicyclic groups
e.g. spiro [4.4] non-2-yl and the like.
[0031] The term "alkoxy" refers to an alkyl group attached via an
oxygen linkage to the rest of the molecule, which may be optionally
substituted by one or more substituents. Preferred alkoxy groups,
without limitation, include --OCH.sub.3, --OC.sub.2H.sub.5 and the
like.
[0032] The term "alkylthio" refers to an alkyl group attached via a
sulfur linkage to the rest of the molecule, which may be optionally
substituted by one or more substituents. Preferred alkylthio
groups, without limitation, include --SCH.sub.3, --SC.sub.2H.sub.5
and the like.
[0033] The term "alkylamino" refers to an alkyl group as defined
above attached via amino linkage to the rest of the molecule, which
may be optionally substituted by one or more substituent's.
Preferred alkylamino groups, without limitation include-NHCH.sub.3,
--N(CH.sub.3).sub.2, and the like.
[0034] The term "alkenyl" refers to an aliphatic hydrocarbon group
containing a carbon-carbon double bond and which may be straight or
branched chain having about 2 to 10 carbon atoms, which may be
optionally substituted by one or more substituent's. Preferred
alkenyl groups, without limitation, include ethenyl, 1-propenyl,
2-propenyl, iso-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl
and the like.
[0035] The term "alkynyl" refers to a straight or branched
hydrocarbyl radicals having at least one carbon-carbon triple bond
and having in the range of 2-12 carbon atoms, which may be
optionally substituted by one or more substituent's. Preferred
alkynyl groups include, without limitation, ethynyl, propynyl,
butynyl and the like.
[0036] "Halo" or "Halogen", alone or in combination with any other
term means halogens such as chloro (Cl), fluoro (F), bromo (Br) and
iodo (I).
[0037] Furthermore, the compound of formula (I) can be its
derivatives, analogs, tautomeric forms, stereoisomer's,
diastereomers, geometrical isomers, polymorphs, solvates,
intermediates, metabolites, prodrugs or pharmaceutically acceptable
salts and compositions.
[0038] The compounds described herein may contain one or more
chiral centers and/or double bonds and therefore, may exist as
stereoisomers, such as double-bond isomers (i.e., geometric
isomers), regioisomers, enantiomers or diastereomers. Accordingly,
the chemical structures depicted herein encompass all possible
enantiomers and stereoisomers of the illustrated or identified
compounds including the stereoisomerically pure form (e.g.,
geometrically pure, enantiomerically pure or diastereomerically
pure) and enantiomeric and stereoisomeric mixtures. Enantiomeric
and stereoisomeric mixtures can be resolved into their component
enantiomers or stereoisomers using separation techniques or chiral
synthesis techniques well known to the person skilled in the art.
The compounds may also exist in several tautomeric forms including
the enol form, the keto form and mixtures thereof. Accordingly, the
chemical structures depicted herein encompass all possible
tautomeric forms of the illustrated or identified compounds. It is
also understood that some isomeric form such as diastereomers,
enantiomers and geometrical isomers can be separated by physical
and/or chemical methods and by those skilled in the art.
Pharmaceutically acceptable solvates may be hydrates or comprising
of other solvents of crystallization such as alcohols, ether, and
the like.
[0039] The term "solvate", as used herein, refers to a crystal form
of a substance which contains solvent.
[0040] The term "hydrate" refers to a solvate wherein the solvent
is water.
[0041] The phrase "pharmaceutical acceptable" refers to compounds
or compositions that are physiologically tolerable and do not
typically produce allergic or similar untoward reaction, including
but not limited to gastric upset or dizziness when administered to
mammal.
[0042] Pharmaceutically acceptable salts forming part of this
invention include salts derived from inorganic bases such as like
Li, Na, K, Ca, Mg, Fe, Cu, Zn and Mn; salts of organic bases such
as N, N'-diacetylethylenediamine, glucamine, triethylamine,
choline, dicyclohexylamine, benzylamine, trialkylamine, thiamine,
guanidine, diethanolamine, .alpha.-phenylethylamine, piperidine,
morpholine, pyridine, hydroxyethylpyrrolidine,
hydroxyethylpiperidine, ammonium, substituted ammonium salts,
aluminum salts and the like. Salts also include amino acid salts
such as glycine, alanine, cystine, cysteine, lysine, arginine,
phenylalanine, guanidine etc. Salts may include acid addition salts
where appropriate which are sulphates, nitrates, phosphates,
perchlorates, borates, hydrohalides, acetates, tartrates, maleates,
citrates, succinates, palmoates, methanesulphonates, tosylates,
benzoates, salicylates, hydroxynaphthoates, benzenesulfonates,
ascorbates, glycerophosphates, ketoglutarates and the like.
[0043] As used herein, the term "substituted" is contemplated to
include all permissible substituents of organic compounds. In a
broad aspect, the permissible substituents include acyclic and
cyclic, branched and unbranched, carbocyclic and heterocyclic,
aromatic and nonaromatic substituents of organic compounds.
Illustrative substituents, for example, include those described
herein above. The permissible substituents can be one or more and
the same or different for appropriate organic compounds. For
purposes of this disclosure, the heteroatoms such as nitrogen may
have hydrogen substituents and/or any permissible substituents of
organic compounds described herein which satisfy the valences of
the heteroatoms.
[0044] The term "effective amount" means an amount of a compound or
composition which is sufficient enough to significantly and
positively modify the symptoms and/or conditions to be treated
(e.g., provide a positive clinical response). The effective amount
of an active ingredient for use in a pharmaceutical composition
will vary with the particular condition being treated, the severity
of the condition, the duration of the treatment, the nature of
concurrent therapy, the particular active ingredient(s) being
employed, the particular pharmaceutically-acceptable
excipient(s)/carrier(s) utilized, the route of administration, and
like factors within the knowledge and expertise of the attending
physician
[0045] The compounds described herein can also be prepared in any
solid or liquid physical form, for example the compound can be in a
crystalline form, in amorphous form and have any particle size.
Furthermore, the compound particles may be micronized or nanoized,
or may be agglomerated, particulate granules, powders, oils, oily
suspensions or any other form of solid or liquid physical
forms.
[0046] The compounds described herein may also exhibit
polymorphism. This invention further includes different polymorphs
of the compounds of the present invention.
[0047] The term "polymorphs" refers to crystal forms of the same
molecule, and different polymorphs may have different physical
properties such as, for example, melting temperatures, heats of
fusion, solubilities, dissolution rates and/or vibrational spectra
as a result of the arrangement or conformation of the molecules in
the crystal lattice.
[0048] The term "prodrugs" refers to the precursor of the compound
of formula (I), which on administration undergoes chemical
conversion by metabolic processes before becoming active
pharmacological substances. In general, such prodrugs will be
functional derivatives of a compound of the invention, which are
readily convertible in vivo into a compound of the invention.
[0049] The present disclosure relates to a compound of Formula
I
##STR00007##
[0050] or its stereoisomers, pharmaceutically acceptable salts,
complexes, hydrates, solvates, tautomers, polymorphs, racemic
mixtures, optically active forms and pharmaceutically active
derivative thereof, wherein ---- ---- is a single bond or a double
bond; X is selected from --O-- or --N--; n is 0-6; R.sub.1 is
selected from alkyl or cycloalkyl; R.sub.2 and R.sub.3 are
independently selected from hydrogen, halogen, hydroxy, nitro,
cyano, azido, nitroso, oxo (.dbd.O), thioxo (.dbd.S), --SO.sub.2--,
amino, hydrazino, formyl, alkyl, haloalkyl, alkoxy, haloalkoxy;
arylalkoxy; cycloalkyl, cycloalkyloxy, aryl, heterocyclyl,
heteroaryl, alkylamino, --COOR.sub.a, --C(O)R.sub.b, --C(S)R.sub.a,
--C(O)NR.sub.aR.sub.b, --C(S)NR.sub.aR.sub.b,
--NR.sup.aC(O)NR.sub.bR.sub.c, NR.sub.aC(S)NR.sub.bR.sub.c,
--N(R.sub.a)SOR.sub.b, --N(R.sub.a)SO.sub.2R.sub.b,
--NR.sub.aC(O)OR.sub.b, --NR.sub.aR.sub.b, --NR.sub.aC(O)R.sub.b--,
NR.sub.aC(S)R.sub.b--, --SONR.sub.aR.sub.b--,
--SO.sub.2NR.sub.aR.sub.b--, --OR.sub.a, --OR.sub.aC(O)OR.sub.b--,
--OC(O)NR.sub.aR.sub.b, OC(O)R.sub.a, --OC(O)NR.sub.aR.sub.b--,
--R.sub.aNR.sub.bR.sub.c, --R.sub.aOR.sub.b--, --SR.sub.a,
--SOR.sub.a or --SO.sub.2R.sub.a, wherein R.sub.a, R.sub.b and
R.sup.c are independently selected from hydrogenalkyl, cycloalkyl,
aryl, arylalkyl, heterocyclyl, heteroarylorhetroarylalkyl; R.sub.4
is selected from hydrogen, alkyl, cycloalkyl, cyloalkenyl,
cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl,
heteroaryl, heteroarylalkyl or haloalkyl is selected from hydrogen,
--CH.sub.2OR.sub.5, --COOR.sub.5, --CONR.sub.5R.sub.6,
--NHCOOR.sub.5, --NHCOR.sub.5 or --NHSO.sub.2R.sub.5, and R.sub.5
and R.sub.6 are independently selected from hydrogen, hydroxyl,
aryl, heteroaryl, cycloalkyl or alkyl.
[0051] According to an embodiment, the present disclosure relates
to a compound of the Formula (I) or its stereoisomers,
pharmaceutically acceptable salts, complexes, hydrates, solvates,
tautomers, polymorphs, racemic mixtures, optically active forms and
pharmaceutically active derivative thereof, wherein ---- is a
single bond or a double bond; X is selected from --O-- or --N--; n
is 0-1; R.sub.1 is selected from C.sub.1-C.sub.8 alkyl or
C.sub.3-C.sub.8cycloalkyl; R.sub.2 and R.sub.3 are independently
selected from hydrogen, fluoro, chloro, bromo, iodo, hydroxy,
nitro, cyano, azido, nitroso, oxo (.dbd.O), thioxo (.dbd.S),
--SO.sub.2--, amino, hydrazino, formyl, C.sub.1-C.sub.8alkyl,
C.sub.1-C.sub.8haloalkyl independently substituted with up to three
halogen selected from fluoro, chloro, bromo, or iodo,
C.sub.1-C.sub.8alkoxy, C.sub.1-C.sub.8haloalkoxy;
C.sub.5-C.sub.18arylalkoxy; C.sub.3-C.sub.8cycloalkyl,
C.sub.3-C.sub.8cycloalkyloxy, C.sub.5-C.sub.18aryl,
C.sub.2-C.sub.18heterocyclyl, C.sub.2-C.sub.18heteroaryl,
alkylamino, --COOR.sub.a, --C(O)R.sub.b, --C(S)R.sub.a,
--C(O)NR.sub.aR.sub.b, --C(S)NR.sub.aR.sub.b,
--NR.sup.aC(O)NR.sub.bR.sub.c, NR.sub.aC(S)NR.sub.bR.sub.c,
--N(R.sub.a)SOR.sub.b, --N(R.sub.a)SO.sub.2R.sub.b,
--NR.sub.aC(O)OR.sub.b, --NR.sub.aR.sub.b, --NR.sub.aC(O)R.sub.b--,
NR.sub.aC(S)R.sub.b--, --SONR.sub.aR.sub.b--,
--SO.sub.2NR.sub.aR.sub.b--, --OR.sub.a, --OR.sub.aC(O)OR.sub.b--,
--OC(O)NR.sub.aR.sub.b, OC(O)R.sub.a, --OC(O)NR.sub.aR.sub.b--,
--R.sub.aNR.sub.bR.sub.c, --R.sub.aOR.sub.b--, --SR.sub.a,
--SOR.sub.a or --SO.sub.2R.sub.a, wherein R.sub.a, R.sub.b and
R.sup.c are independently selected from hydrogen, C.sub.1-C.sub.8
alkyl, C.sub.3-C.sub.8cycloalkyl, C.sub.5-C.sub.18 aryl,
C.sub.5-C.sub.18 arylalkyl, C.sub.2-C.sub.18heterocyclyl,
C.sub.2-C.sub.18heteroaryl and C.sub.2-C.sub.18hetroarylalkyl;
R.sub.4 is selected from hydrogen, C.sub.1-C.sub.8alkyl,
C.sub.2-C.sub.8alkynyl, C.sub.3-C.sub.8cycloalkyl,
C.sub.3-C.sub.8cyloalkenyl, C.sub.3-C.sub.8cycloalkylalkyl,
C.sub.5-C.sub.18 aryl, C.sub.5-C.sub.18 arylalkyl,
C.sub.2-C.sub.18heterocyclyl, C.sub.2-C.sub.18heterocyclylalkyl,
C.sub.2-C.sub.18heteroaryl, C.sub.2-C.sub.18heteroarylalkyl or
C.sub.1-C.sub.8haloalkyl, wherein alkyl, cycloalkyl, cycloalkenyl,
cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl,
heteroaryl and heteroarylalkyl are independently unsubstituted or
substituted with up to three substituents independently selected
from halogen, alkyl, alkenyl, alkynyl, alkoxy, acyl, acyloxy,
amino, hydroxy, keto, nitro, azido, cyano, amide, sulfonamide and
carbamate, wherein the heterocyclyl, heterocyclylalkyl, heteroaryl
and heteroarylalkyl contains up to three heteroatoms selected from
O, N or S; Z is selected from hydrogen, --CH.sub.2OR.sub.5,
--COOR.sub.5, --CONR.sub.5R.sub.6, --NHCOOR.sub.5, --NHCOR.sub.5 or
--NHSO.sub.2R.sub.5, wherein R.sub.5 and R.sub.6 are independently
selected from hydrogen, hydroxyl, C.sub.5-C.sub.18aryl,
C.sub.2-C.sub.18heteroaryl, C.sub.3-C.sub.8cycloalkyl or
C.sub.1-C.sub.8alkyl; wherein R.sub.5 and R.sub.6 are optionally
substituted with one or more substituents selected from fluorine,
chlorine, bromine, iodine, hydroxy, nitro, cyano, azido, nitroso,
oxo (.dbd.O), thioxo (.dbd.S), --SO.sub.2--, amino, hydrazino,
formyl, C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8haloalkylalkoxy,
C.sub.1-C.sub.8haloalkoxy; C.sub.5-C.sub.18 arylalkoxy;
C.sub.3-C.sub.8cycloalkyl, C.sub.3-C.sub.8cycloalkyloxy,
C.sub.5-C.sub.18aryl, C.sub.2-C.sub.18heterocyclyl,
C.sub.2-C.sub.18heteroaryl, alkylamino, --COOR.sup.a,
--C(O)R.sup.b, --C(S)R.sup.a, --C(O)NR.sup.aR.sup.b,
--C(S)NR.sup.aR.sup.b, --NR.sup.aC(O)NR.sup.bR.sup.c,
NR.sup.aC(S)NR.sup.bR.sup.c, --N(R.sup.a)SOR.sup.b,
--N(R.sup.a)SO.sub.2R.sup.b, --NR.sup.aC(O)OR.sup.b,
--NR.sup.aR.sup.b, --NR.sup.aC(O)R.sup.b--, NR.sup.aC(S)R.sup.b--,
--SONR.sup.aR.sup.b--, --SO.sub.2NR.sup.aR.sup.b--, --OR.sup.a,
--OR.sup.aC(O)OR.sup.b--, --OC(O)NR.sup.aR.sup.b, OC(O)R.sup.a,
--OC(O)NR.sup.aR.sup.b--, --R.sup.aNR.sup.bR.sup.c,
--R.sup.aOR.sup.b--, --SR.sup.a, --SOR.sup.a or --SO.sub.2R.sup.a,
wherein R.sup.a, R.sup.b and R.sup.c are independently selected
from hydrogen, or optionally substituted groups selected from
alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl,
heteroarylorhetroarylalkyl.
[0052] According to another embodiment, the present disclosure
relates to the compound of Formula (1) or its stereoisomers,
pharmaceutically acceptable salts, complexes, hydrates, solvates,
tautomers, polymorphs, racemic mixtures, optically active forms and
pharmaceutically active derivative thereof, wherein, ---- is a
single bond or a double bond; X is selected from --O-- or --N--; n
is 0-1; R.sub.1 is selected from hydrogen, methyl, ethyl, n-propyl,
ispopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl,
octyl, cyclopropyl, cyclobutyl, cyclopentylorcyclohexyl; R.sub.2
and R.sub.3 are independently selected from hydrogen, fluorine,
chlorine, bromine, iodine; hydroxy, nitro, cyano, azido, nitroso,
oxo (.dbd.O), thioxo (.dbd.S), --SO.sub.2--, amino, hydrazino,
formyl, alkyl, haloalkyl group such as trifluoromethyl,
tribromomethyl, trichloromethyl and the like; alkoxy, haloalkoxy
such as --OCH.sub.2Cl and the like; arylalkoxy such as benzyloxy,
phenylethoxy and the like; cycloalkyl, cycloalkyloxy, aryl,
heterocyclyl, heteroaryl, alkylamino, --COOR.sub.a, --C(O)R.sub.b,
--C(S)R.sub.a, --C(O)NR.sub.aR.sub.b, --C(S)NR.sub.aR.sub.b,
--NR.sup.aC(O)NR.sub.bR.sub.c, NR.sub.aC(S)NR.sub.bR.sub.c,
--N(R.sub.a)SOR.sub.b, --N(R.sub.a)SO.sub.2R.sub.b,
--NR.sub.aC(O)OR.sub.b, --NR.sub.aR.sub.b, --NR.sub.aC(O)R.sub.b--,
NR.sub.aC(S)R.sub.b--, --SONR.sub.aR.sub.b--,
--SO.sub.2NR.sub.aR.sub.b--, --OR.sub.a, --OR.sub.aC(O)OR.sub.b--,
--OC(O)NR.sub.aR.sub.b, OC(O)R.sub.a, --OC(O)NR.sub.aR.sub.b--,
--R.sub.aNR.sub.bR.sub.c, --R.sub.aOR.sub.b--, --SR.sub.a,
--SOR.sub.a or --SO.sub.2R.sub.a, wherein R.sub.a, R.sub.b and
R.sub.c are independently selected from hydrogen, alkyl,
cycloalkyl, aryl, arylalkyl, heterocyclyl, heteroaryl and
hetroarylalkyl. R.sub.4 is selected from hydrogen and a substituted
or unsubstituted aryl comprising of phenyl, naphthyl, biphenyl and
indanyl; heteroaryl comprising of pyridinyl, pyridazinyl,
pyrimidyl, triazinyl, pyrrolyl, indolyl, pyrazolyl, imidazolyl,
pyrazinyl, pyrimidinyl, tetrazolyl, furyl, thienyl, thiazolyl,
isoxazolyl, oxazolyl and quinolinyl; cycloalkyl group comprising of
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclooctyl; an
alkyl group comprising of methyl, ethyl, n-propyl, isopropyl,
butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl and octyl;
haloalkyl group comprising of trichloromethyl, trifluoromethyl,
difluoromethyl, trifluoroethyl, trichloroethyl, monofluoromethyl or
monochloromethyl; Z is selected from hydrogen, --CH.sub.2OR.sub.5,
--COOR.sub.5, --CONR.sub.5R.sub.6, --NHCOOR.sub.5, --NHCOR.sub.5,
or --NHSO.sub.2R.sub.5, wherein R.sub.5 and R.sub.6 are selected
from hydrogen or substituted or unsubstituted aryl comprising
phenyl, naphthyl, biphenyl and indanyl: heteroaryl comprising of
pyridinyl, pyridazinyl, pyrimidyl, triazinyl, pyrrolyl, indolyl,
pyrazolyl, imidazolyl, pyrazinyl, pyrimidinyl, tetrazolyl, furyl,
thienyl, thiazolyl, isoxazolyl, oxazolyl and quinolinyl; cycloalkyl
group comprising of cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl and cyclooctyl; an alkyl group comprising of methyl,
ethyl, n-propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl,
hexyl, heptyl and octyl; R.sub.5 and R.sub.6 are optionally
substituted with one or more selected from but not limited to
halogens such as fluorine, chlorine, bromine, iodine; hydroxy,
nitro, cyano, azido, nitroso, oxo (.dbd.O), thioxo (.dbd.S),
--SO.sub.2--, amino, hydrazino, formyl, alkyl, haloalkyl group such
as trifluoromethyl, tribromomethyl, trichloromethyl and the like;
alkoxy, haloalkoxy such as --OCH.sub.2Cl and the like; arylalkoxy
such as benzyloxy, phenylethoxy and the like; cycloalkyl,
cycloalkyloxy, aryl, heterocyclyl, heteroaryl, alkylamino,
--COOR.sup.a, --C(O)R.sup.b, --C(S)R.sup.a, --C(O)NR.sup.aR.sup.b,
--C(S)NR.sup.aR.sup.b, --NR.sup.aC(O)NR.sup.bR.sup.c,
NR.sup.aC(S)NR.sup.bR.sup.c, --N(R.sup.a)SOR.sup.b,
--N(R.sup.a)SO.sub.2R.sup.b, --NR.sup.aC(O)OR.sup.b,
--NR.sup.aR.sup.b, --NR.sup.aC(O)R.sup.b--, NR.sup.aC(S)R.sup.b--,
--SONR.sup.aR.sup.b--, --SO.sub.2NR.sup.aR.sup.b--, --OR.sup.a,
--OR.sup.aC(O)OR.sup.b--, --OC(O)NR.sup.aR.sup.b, OC(O)R.sup.a,
--OC(O)NR.sup.aR.sup.b--, --R.sup.aNR.sup.bR.sup.c,
--R.sup.aOR.sup.b--, --SR.sup.a, --SOR.sup.a or --SO.sub.2R.sup.a,
wherein R.sup.a, R.sup.b and R.sup.c are independently selected
from hydrogen, or optionally substituted groups selected from
alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl,
heteroarylorhetroarylalkyl.
[0053] According to an embodiment, the present disclosure relates
to the compound of Formula (1) or its stereoisomers,
pharmaceutically acceptable salts, complexes, hydrates, solvates,
tautomers, polymorphs, racemic mixtures, optically active forms and
pharmaceutically active derivative thereof, wherein, ---- is a
single bond; X is --O--; n is 0-1; R.sub.1 is selected from
C.sub.1-C.sub.8 alkyl or C.sub.3-C.sub.8cycloalkyl; R.sub.2 is
hydrogen; R.sub.3 is selected from halogen, C.sub.1-C.sub.8 alkyl,
C.sub.1-C.sub.8haloalkyl substituted up to 3 halogen selected from
fluoro, chloro, bromo, oriodo, C.sub.1-C.sub.8alkoxy,
C.sub.1-C.sub.8haloalkoxy; C.sub.5-C.sub.18arylalkoxy;
C.sub.3-C.sub.8cycloalkyl, C.sub.3-C.sub.8cycloalkyloxy,
C.sub.5-C.sub.18 aryl, C.sub.2-C.sub.18heterocyclyl or
C.sub.2-C.sub.18heteroaryl; R.sub.4 is selected from hydrogen,
C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.8cycloalkyl,
C.sub.3-C.sub.8cyloalkenyl, C.sub.3-C.sub.8cycloalkylalkyl,
C.sub.5-C.sub.18 aryl, C.sub.5-C.sub.18arylalkyl,
C.sub.2-C.sub.18heterocyclyl, C.sub.2-C.sub.18heterocyclylalkyl,
C.sub.2-C.sub.18heteroaryl, C.sub.2-C.sub.18 heteroarylalkyl or
C.sub.1-C.sub.8haloalkyl, wherein alkyl, cycloalkyl, cycloalkenyl,
cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl,
heteroaryl and heteroarylalkyl are independently unsubstituted or
substituted with up to three substituents independently selected
from halogen, alkyl, alkenyl, alkynyl, alkoxy, acyl, acyloxy,
amino, hydroxy, keto, nitro, azido, cyano, amide, sulfonamide and
carbamate; wherein the heterocyclyl, heterocyclylalkyl, heteroaryl
and heteroarylalkyl contains up to three heteroatoms selected from
O, N or S; Z is selected from the group consisting of hydrogen,
--CH.sub.2OR.sub.5, --COOR.sub.5, --CONR.sub.5R.sub.6,
--NHCOOR.sub.5, --NHCOR.sub.5 or --NHSO.sub.2R.sub.5, wherein
R.sub.5 and R.sub.6 are independently selected from hydrogen,
hydroxyl, C.sub.5-C.sub.18 aryl, C.sub.2-C.sub.18heteroaryl,
C.sub.3-C.sub.8cycloalkyl or C.sub.1-C.sub.8 alkyl; wherein R.sub.5
and R.sub.6 are optionally substituted with one or more
substituents selected fluorine, chlorine, bromine, iodine; hydroxy,
nitro, cyano, azido, nitroso, oxo (.dbd.O), thioxo (.dbd.S),
--SO.sub.2--, amino, hydrazino, formyl, C.sub.1-C.sub.8 alkyl,
C.sub.1-C.sub.8haloalkylalkoxy, C.sub.1-C.sub.8haloalkoxy;
C.sub.5-C.sub.18arylalkoxy; C.sub.3-C.sub.8cycloalkyl,
C.sub.3-C.sub.8cycloalkyloxy, C.sub.6-C.sub.18 aryl,
C.sub.2-C.sub.18heterocyclyl or C.sub.2-C.sub.18heteroaryl.
[0054] According to an embodiment, the present disclosure relates
to the compound of Formula (1) or its stereoisomers,
pharmaceutically acceptable salts, complexes, hydrates, solvates,
tautomers, polymorphs, racemic mixtures, optically active forms and
pharmaceutically active derivative thereof, wherein, ---- is a
single bond or a double bond; X is selected from --O-- or --N--; n
is 0-1; R.sub.1 is selected from C.sub.1-C.sub.2 alkyl; R.sub.2 and
R.sub.3 are independently selected from hydrogen, halogen,
C.sub.1-C.sub.8 haloalkyl, C.sub.1-C.sub.8alkoxy, and
C.sub.1-C.sub.8 haloalkoxy; R.sub.4 is selected from hydrogen,
C.sub.1-C.sub.8alkyl, C.sub.2-C.sub.8alkynyl,
C.sub.3-C.sub.8cycloalkyl, C.sub.3-C.sub.8cycloalkylalkyl,
C.sub.5-C.sub.18aryl, C.sub.2-C.sub.18heteroaryl, or
C.sub.1-C.sub.8haloalkyl, wherein alkyl, cycloalkyl,
cycloalkylalkyl, aryl, heteroaryl and heteroarylalkyl are
independently unsubstituted or substituted with up to three
substituents independently selected from halogen, alkyl, and cyano,
wherein the heteroaryl contains up to three heteroatoms selected
from 0 or N; Z is selected from hydrogen, --CH.sub.2OR.sub.5,
--COOR.sub.5, --CONR.sub.5R.sub.6, --NHCOOR.sub.5, -- or
NHCOR.sub.5, wherein R.sub.5 and R.sub.6 are independently selected
from hydrogen, C.sub.5-C.sub.18aryl, or C.sub.1-C.sub.8alkyl;
wherein R.sub.5 and R.sub.6 are optionally substituted with one or
more substituents selected from fluorine, chlorine, bromine,
iodine, hydroxy, and cyano.
[0055] According to an embodiment, the present disclosure relates
to the compound of Formula (1) or its stereoisomers,
pharmaceutically acceptable salts, complexes, hydrates, solvates,
tautomers, polymorphs, racemic mixtures, optically active forms and
pharmaceutically active derivative thereof, wherein, is a single
bond or a double bond; X is selected from --O-- or --N--; n is 0-1;
R.sub.1 is selected from methyl and isopropyl; R.sub.2 is hydrogen;
R.sub.3 is selected from, halogen, C.sub.1-C.sub.2 haloalkyl,
C.sub.1-C.sub.2 alkoxy, and C.sub.1-C.sub.2 haloalkoxy; wherein
haloalkyl and haloalkoxy are substituted with one or more
substituents selected from fluorine and chlorine; R.sub.4 is
selected from hydrogen, C.sub.1-C.sub.2alkyl,
C.sub.3-C.sub.5cycloalkyl, C.sub.3-C.sub.5cycloalkylalkyl,
C.sub.5-C.sub.6 aryl, C.sub.5-C.sub.6heteroaryl, or
C.sub.1-C.sub.2haloalkyl, wherein alkyl, cycloalkylalkyl, aryl,
heteroaryl and heteroarylalkyl are independently unsubstituted or
substituted with up to three substituents independently selected
from halogen, alkyl, cyano amide, sulfonamide and carbamate,
wherein the heteroaryl contains one heteroatom as N; Z is selected
from hydrogen, --CH.sub.2OR.sub.5, --COOR.sub.5,
--CONR.sub.5R.sub.6, --NHCOOR.sub.5, -- or NHCOR.sub.5, wherein
R.sub.5 and R.sub.6 are independently selected from hydrogen,
C.sub.6 aryl, or C.sub.1-C.sub.3alkyl; wherein C.sub.6 aryl is
substituted with hydroxyl.
[0056] According to another embodiment, the present disclosure
relates to the compound of Formula (1) or its stereoisomers,
pharmaceutically acceptable salts, complexes, hydrates, solvates,
tautomers, polymorphs, racemic mixtures, optically active forms and
pharmaceutically active derivative thereof, wherein, ---- is a
single bond; X is --O--; n is 0-1; R.sub.1 is selected from
C.sub.1-C.sub.8 alkyl or C.sub.3-C.sub.8cycloalkyl; R.sub.2 is
hydrogen; R.sub.3 is selected from halogen, C.sub.1-C.sub.8 alkyl,
C.sub.1-C.sub.8haloalkyl substituted up to 3 halogen selected from
fluoro, chloro, bromo, oriodo, C.sub.1-C.sub.8alkoxy,
C.sub.1-C.sub.8haloalkoxy; C.sub.5-C.sub.18arylalkoxy;
C.sub.3-C.sub.8cycloalkyl, C.sub.3-C.sub.8cycloalkyloxy,
C.sub.5-C.sub.18 aryl, C.sub.2-C.sub.18heterocyclyl or
C.sub.2-C.sub.18heteroaryl; R.sub.4 is selected from hydrogen,
C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.8cycloalkyl, C.sub.5-C.sub.18
aryl, C.sub.5-C.sub.18arylalkyl, C.sub.2-C.sub.18heterocyclyl,
C.sub.2-C.sub.18heteroaryl, C.sub.2-C.sub.18heteroarylalkyl or
C.sub.1-C.sub.8haloalkyl, wherein alkyl, cycloalkyl, aryl,
arylalkyl, heterocyclyl, heteroaryl and heteroarylalkyl are
independently unsubstituted or substituted with up to three
substituents independently selected from halogen, alkyl, alkenyl,
alkynyl, alkoxy, acyl, acyloxy, amino, hydroxy, keto, nitro, azido,
cyano; wherein the heterocyclyl, heteroaryl and heteroarylalkyl
contains up to three heteroatoms selected from O, N or S; Z is
selected from the group consisting of hydrogen, --CH.sub.2OR.sub.5,
--COOR.sub.5, --CONR.sub.5R.sub.6, --NHCOOR.sub.5, --NHCOR.sub.5 or
--NHSO.sub.2R.sub.5, R.sub.5 and R.sub.6 are independently selected
from hydrogen, hydroxyl, C.sub.5-C.sub.18 aryl,
C.sub.2-C.sub.18heteroaryl, C.sub.3-C.sub.8cycloalkyl or
C.sub.1-C.sub.8 alkyl; wherein R.sub.5 and R.sub.6 are optionally
substituted with one or more substituents selected from fluorine,
chlorine, bromine, iodine; hydroxy, nitro, cyano, azido, nitroso,
oxo (.dbd.O), thioxo (.dbd.S), --SO.sub.2--, amino, hydrazino,
formyl, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8haloalkylalkoxy,
C.sub.1-C.sub.8haloalkoxy; C.sub.5-C.sub.18arylalkoxy;
C.sub.3-C.sub.8cycloalkyl, C.sub.3-C.sub.8cycloalkyloxy,
C.sub.6-C.sub.18 aryl, C.sub.2-C.sub.18heterocyclyl or
C.sub.2-C.sub.18heteroaryl.
[0057] According to an embodiment, the present disclosure relates
to the compound of Formula (1) or its stereoisomers,
pharmaceutically acceptable salts, complexes, hydrates, solvates,
tautomers, polymorphs, racemic mixtures, optically active forms and
pharmaceutically active derivative thereof, wherein, ---- is a
double bond; X is --N--; n is 0-1; R.sub.1 is selected from
C.sub.1-C.sub.8 alkyl or C.sub.3-C.sub.8 cycloalkyl; R.sub.2 is
hydrogen; R.sub.3 is selected from halogen, C.sub.1-C.sub.8 alkyl,
C.sub.1-C.sub.8haloalkyl substituted up to three halogen selected
from fluoro, chloro, bromo, or iodo, C.sub.1-C.sub.8alkoxy,
C.sub.1-C.sub.8haloalkoxy; C.sub.5-C.sub.18arylalkoxy;
C.sub.3-C.sub.8cycloalkyl, C.sub.3-C.sub.8cycloalkyloxy,
C.sub.5-C.sub.18 aryl, C.sub.2-C.sub.18heterocyclyl or
C.sub.2-C.sub.18heteroaryl; R.sub.4 is selected from hydrogen,
C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.8cycloalkyl,
C.sub.3-C.sub.8cyloalkenyl, C.sub.3-C.sub.8 cycloalkylalkyl,
C.sub.5-C.sub.18 aryl, C.sub.5-C.sub.18arylalkyl,
C.sub.2-C.sub.18heterocyclyl, C.sub.2-C.sub.18heterocyclylalkyl,
C.sub.2-C.sub.18heteroaryl, C.sub.2-C.sub.18heteroaryl alkyl or
C.sub.1-C.sub.8haloalkyl; wherein alkyl, cycloalkyl, cycloalkenyl,
cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl,
heteroaryl and heteroarylalkyl are independently unsubstituted or
substituted with up to three substituents independently selected
from halogen, alkyl, alkenyl, alkynyl, alkoxy, acyl, acyloxy,
amino, hydroxy, keto, nitro, azido, cyano; wherein the
heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl
contains up to three heteroatoms selected from O, N or S; Z is
selected from the group consisting of hydrogen, --CH.sub.2OR.sub.5,
--COOR.sub.5, --CONR.sub.5R.sub.6, --NHCOOR.sub.5, --NHCOR.sub.5 or
--NHSO.sub.2R.sub.5, R.sub.5 and R.sub.6 are independently selected
from hydrogen, hydroxyl, C.sub.5-C.sub.18 aryl,
C.sub.2-C.sub.18heteroaryl, C.sub.3-C.sub.8cycloalkyl or
C.sub.1-C.sub.8 alkyl; wherein R.sub.5 and R.sub.6 are optionally
substituted with, the one or more substituents are selected from
but not limited to halogens such as fluorine, chlorine, bromine,
iodine; hydroxy, nitro, cyano, azido, nitroso, oxo (.dbd.O), thioxo
(.dbd.S), --SO.sub.2--, amino, hydrazino, formyl, C.sub.1-C.sub.8
alkyl, C1-C8 haloalkylalkoxy, C.sub.1-C.sub.8 haloalkoxy;
C.sub.5-C.sub.18 arylalkoxy; C.sub.3-C.sub.8 cycloalkyl,
C.sub.3-C.sub.8 cycloalkyloxy, C.sub.6-C.sub.18 aryl,
C.sub.2-C.sub.18 heterocyclyl or C.sub.2-C.sub.18 heteroaryl.
[0058] According to an embodiment, the present disclosure relates
to the compound of Formula (1) or its stereoisomers,
pharmaceutically acceptable salts, complexes, hydrates, solvates,
tautomers, polymorphs, racemic mixtures, optically active forms and
pharmaceutically active derivative thereof, wherein, ---- is a
double bond; X is --N--; n is 0-1; R.sub.1 is selected from
C.sub.1-C.sub.8 alkyl or C.sub.3-C.sub.8 cycloalkyl; R.sup.2 is
hydrogen; R.sup.3 is selected from halogen, C.sub.1-C.sub.8 alkyl,
C.sub.1-C.sub.8 haloalkyl substituted up to 3 halogen selected from
fluoro, chloro, bromo, iodo, C.sub.1-C.sub.8 alkoxy,
C.sub.1-C.sub.8 haloalkoxy; C.sub.5-C.sub.18 arylalkoxy;
C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8 cycloalkyloxy,
C.sub.6-C.sub.18 aryl, C.sub.2-C.sub.18 heterocyclyl or
C.sub.5-C.sub.18 heteroaryl; R.sub.4 is selected from hydrogen,
C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.5-C.sub.18
aryl, C.sub.5-C.sub.18 arylalkyl, C.sub.2-C.sub.18 heterocyclyl,
C.sub.2-C.sub.18 heteroaryl, C.sub.2-C.sub.18 heteroarylalkyl or
C.sub.1-C.sub.8 haloalkyl; wherein alkyl, cycloalkyl, aryl,
arylalkyl, heterocyclyl, heteroaryl and heteroarylalkyl are
independently unsubstituted or substituted with up to three
substituents independently selected from halogen, alkyl, alkenyl,
alkynyl, alkoxy, acyl, acyloxy, amino, hydroxy, keto, nitro, azido,
cyano; wherein the heterocyclyl, heteroaryl and heteroarylalkyl
contains up to three heteroatoms selected from O, N or S; Z is
selected from the group consisting of hydrogen, --CH.sub.2OR.sub.5,
--COOR.sub.5, --CONR.sub.5R.sub.6, --NHCOOR.sub.5, or --NHCOR.sub.5
wherein; R.sub.5 and R.sub.6 are independently selected from
hydrogen, hydroxyl, C.sub.6-C.sub.18 aryl, C.sub.2-C.sub.18
heteroaryl, C.sub.3-C.sub.8 cycloalkyl or C.sub.1-C.sub.8 alkyl
wherein; R.sub.5 and R.sub.6 are optionally substituted, with one
or more substituents selected from fluorine, chlorine, bromine,
iodine; hydroxy, nitro, cyano, azido, nitroso, oxo (.dbd.O), thioxo
(.dbd.S), --SO.sub.2--, amino, hydrazino, formyl, C.sub.1-C.sub.8
alkyl, C.sub.1-C.sub.8 haloalkylalkoxy, C.sub.1-C.sub.8 haloalkoxy;
C.sub.5-C.sub.18 arylalkoxy; C.sub.3-C.sub.8 cycloalkyl,
C.sub.3-C.sub.8 cycloalkyloxy, C.sub.5-C.sub.18 aryl,
C.sub.2-C.sub.18 heterocyclyl or C.sub.2-C.sub.18 heteroaryl.
[0059] According to another embodiment, the present disclosure
relates to the compound of the Formula (Ia),
##STR00008##
or its stereoisomers, pharmaceutically acceptable salts, complexes,
hydrates, solvates, tautomers, polymorphs, racemic mixtures,
optically active forms and pharmaceutically active derivative
thereof, wherein X is selected from --O-- or --N--; n is 0-1; R1 is
selected from C1-C8 alkyl or C3-C8 cycloalkyl; R2 and R3 are
independently selected from hydrogen, fluoro, chloro, bromo, iodo,
hydroxy, nitro, cyano, azido, nitroso, oxo (.dbd.O), thioxo
(.dbd.S), --SO2-, amino, hydrazino, formyl, C1-C8 alkyl,
C1-C8haloalkyl independently substituted with up to 3 halogen
selected from fluoro, chloro, bromo, or iodo, C1-C8alkoxy,
C1-C8haloalkoxy; C5-C18arylalkoxy; C3-C8cycloalkyl,
C3-C8cycloalkyloxy, C5-C18 aryl, C2-C18heterocyclyl,
C2-C18heteroaryl, alkylamino, --COORa, --C(O)Rb, --C(S)Ra,
--C(O)NRaRb, --C(S)NRaRb, --NRaC(O)NRbRc, NRaC(S)NRbRc,
--N(Ra)SORb, --N(Ra)SO2Rb, --NRaC(O)ORb, --NRaRb, --NRaC(O)Rb--,
NRaC(S)Rb--, --SONRaRb--, --SO2NRaRb--, --ORa, --ORaC(O)ORb--,
--OC(O)NRaRb, OC(O)Ra, --OC(O)NRaRb--, --RaNRbRc, --RaORb--, --SRa,
--SORa or --SO2Ra, wherein Ra, Rb and Rc are independently selected
from hydrogen, C1-C8 alkyl, C3-C8cycloalkyl, C5-C18aryl,
C5-C18arylalkyl, C2-C18heterocyclyl, C2-C18heteroaryl and
C2-C18hetroarylalkyl. R4 is selected from hydrogen, C1-C8 alkyl,
C3-C8 cycloalkyl, C6-C18aryl or C2-C18heteroaryl; wherein alkyl,
cycloalkyl, aryl, and heteroaryl are independently unsubstituted or
substituted with up to three substituents independently selected
from halogen, alkyl, alkenyl, alkynyl, alkoxy, acyl, acyloxy,
amino, hydroxy, keto, nitro, azido, cyano; wherein the heteroaryl
contains up to three heteroatoms selected from O, N or S; Z is
selected from --CH2OR5, --COOR5, --CONR5R6, or --CONHR7; R5 and R6
are independently selected from hydrogen, hydroxyl, C5-C18 aryl,
C2-C18heteroaryl, C3-C8cycloalkyl or C1-C8 alkyl; wherein R5 and R6
are optionally substituted, with one or more substituents selected
from fluorine, chlorine, bromine, iodine; hydroxy, nitro, cyano,
azido, nitroso, oxo (.dbd.O), thioxo (.dbd.S), --SO2-, amino,
hydrazino, formyl, C1-C8 alkyl, C1-C8 haloalkylalkoxy, C1-C8
haloalkoxy; C5-C18 arylalkoxy; C3-C8 cycloalkyl, C3-C8
cycloalkyloxy, C5-C18 aryl, C2-C18 heterocyclyl, C2-C18 heteroaryl,
alkylamino, --COORa, --C(O)Rb, --C(S)Ra, --C(O)NRaRb, --C(S)NRaRb,
--NRaC(O)NRbRc, NRaC(S)NRbRc, --N(Ra)SORb, --N(Ra)SO2Rb,
--NRaC(O)ORb, --NRaRb, --NRaC(O)Rb--, NRaC(S)Rb--, --SONRaRb--,
--SO2NRaRb--, --ORa, --ORaC(O)ORb--, --OC(O)NRaRb, OC(O)Ra,
--OC(O)NRaRb--, --RaNRbRc, --RaORb--, --SRa, --SORa or --SO2Ra,
wherein Ra, Rb and Rc are independently selected from hydrogen, or
optionally substituted groups selected from alkyl, cycloalkyl,
aryl, arylalkyl, heterocyclyl, heteroarylorhetroarylalkyl. R7
represents -0R8, ortho substituted aniline, amino aryl and amino
heteroaryl, which may be further substituted, wherein R8 is
selected from hydrogen, optionally substituted groups selected from
alkyl, aryl, heterocyclyl and --COR9, wherein R9 is selected from
alkyl, aryl, heteroaryl, cycloalkylorheterocyclyl.
[0060] According to an embodiment, the present disclosure relates
to a compound of Formula Ia
##STR00009##
their analogs, tautomeric forms, stereoisomers, polymorphs,
solvates, intermediates, pharmaceutically acceptable salts,
pharmaceutical compositions, metabolites and prodrugs thereof which
can be used for the treatment of proliferative diseases; wherein,
R.sub.1 represents substituted or unsubstituted alkyl or
cycloalkyl; X represents --O-- or --N--; R.sub.4 represent hydrogen
or substituted or unsubstituted aryl, heteroaryl, cycloalkyl and
alkyl; Z represents --CH.sub.2OR.sub.5, --COOR.sub.5 or
--CONR.sub.5R.sub.6, --CONHR.sub.7, R.sub.5 and R.sub.6 represent
hydrogen or substituted or unsubstituted aryl, heteroaryl,
cycloalkyl and alkyl; R.sub.7 represents --OR.sub.8, ortho
substituted aniline, amino aryl and amino heteroaryl, which may be
further substituted, wherein R.sub.8 represents hydrogen,
optionally substituted groups selected from alkyl, aryl,
heterocyclyl and --COR.sub.9, wherein R.sub.9 represents optionally
substituted groups selected from alkyl, aryl, heteroaryl,
cycloalkyl and heterocyclyl; n represents an integer from 0-6;
R.sub.2 and R.sub.3 represent substitution which are independently
selected from hydrogen, be one or more are selected from but not
limited to halogens such as fluorine, chlorine, bromine, iodine;
hydroxy, nitro, cyano, azido, nitroso, oxo (.dbd.O), thioxo
(.dbd.S), --SO.sub.2--, amino, hydrazino, formyl, alkyl, haloalkyl
group such as trifluoromethyl, tribromomethyl, trichloromethyl and
the like; alkoxy, haloalkoxy such as --OCH.sub.2C1 and the like;
arylalkoxy such as benzyloxy, phenylethoxy and the like;
cycloalkyl, cycloalkyloxy, aryl, heterocyclyl, heteroaryl,
alkylamino, --COOR.sub.a, --C(O)R.sub.b, --C(S)R.sub.a,
--C(O)NR.sup.aR.sub.b, --C(S)NR.sub.aR.sub.b,
--NR.sub.aC(O)NR.sub.bR.sub.c, NR.sub.aC(S)NR.sub.bR.sub.c,
--N(R.sub.a)SOR.sub.b, --N(R.sub.a)SO.sub.2R.sub.b,
--NR.sub.aC(O)OR.sub.b, --NR.sub.aR.sub.b, --NR.sub.aC(O)R.sub.b--,
NR.sub.aC(S)R.sub.b--, --SONR.sub.aR.sub.b--,
--SO.sub.2NR.sub.aR.sub.b--, --OR.sub.a, --OR.sub.aC(O)OR.sub.b--,
--OC(O)NR.sub.aR.sub.b, OC(O)R.sub.a, --OC(O)NR.sub.aR.sub.b--,
--R.sub.aNR.sub.bR.sub.c, --R.sub.aOR.sub.b--, --SR.sub.a,
--SOR.sub.a and --SO.sub.2R.sub.a, wherein R.sub.a, R.sub.b and
R.sub.c in each of the above groups can be hydrogen, optionally
substituted groups selected from alkyl, cycloalkyl, aryl,
arylalkyl, heterocyclyl, heteroaryl and hetroarylalkyl. The
substituents are optionally further substituted by one or more
substituents as defined above.
[0061] According to an embodiment, the present disclosure relates
to a compound of Formula I or its stereoisomers, pharmaceutically
acceptable salts, complexes, hydrates, solvates, tautomers,
polymorphs, racemic mixtures, optically active forms and
pharmaceutically active derivative thereof, wherein, R.sub.1 is
methyl or iso-propyl.
[0062] According to an embodiment, the present disclosure relates
to a compound of Formula I or its stereoisomers, pharmaceutically
acceptable salts, complexes, hydrates, solvates, tautomers,
polymorphs, racemic mixtures, optically active forms and
pharmaceutically active derivative thereof, wherein, R.sub.2 is
hydrogen.
[0063] According to an embodiment, the present disclosure relates
to a compound of Formula I or its stereoisomers, pharmaceutically
acceptable salts, complexes, hydrates, solvates, tautomers,
polymorphs, racemic mixtures, optically active forms and
pharmaceutically active derivative thereof, wherein, R.sub.3 is
selected from C.sub.1-C.sub.8alkoxy, C.sub.1-C.sub.8haloalkyl,
halogen or C.sub.1-C.sub.8 haloalkoxy.
[0064] According to an embodiment, the present disclosure relates
to a compound of Formula I or its stereoisomers, pharmaceutically
acceptable salts, complexes, hydrates, solvates, tautomers,
polymorphs, racemic mixtures, optically active forms and
pharmaceutically active derivative thereof, wherein, R.sub.3 is
selected from methoxy, trifluoromethyl, fluorine, or
difluoromethoxy.
[0065] According to an embodiment, the present disclosure relates
to a compound of Formula I or its stereoisomers, pharmaceutically
acceptable salts, complexes, hydrates, solvates, tautomers,
polymorphs, racemic mixtures, optically active forms and
pharmaceutically active derivative thereof, wherein, R.sub.4 is
selected from C1 alkyl, C.sub.3cycloalkyl, C.sub.6 cycloalkyl
C.sub.3cycloalkylalkyl, C.sub.6 aryl, C.sub.5heteroaryl, or
C.sub.1haloalkyl, wherein alkyl, cycloalkylalkyl, aryl, heteroaryl
and heteroarylalkyl are independently unsubstituted or substituted
with up to three substituents independently selected from fluorine,
chlorine, methyl and cyano, wherein the heteroaryl contains one
heteroatom as N.
[0066] According to an embodiment, the present disclosure relates
to a compound of Formula I or its stereoisomers, pharmaceutically
acceptable salts, complexes, hydrates, solvates, tautomers,
polymorphs, racemic mixtures, optically active forms and
pharmaceutically active derivative thereof, wherein, X is
--N--.
[0067] According to an embodiment, the present disclosure relates
to a compound of Formula I or its stereoisomers, pharmaceutically
acceptable salts, complexes, hydrates, solvates, tautomers,
polymorphs, racemic mixtures, optically active forms and
pharmaceutically active derivative thereof, wherein, X is
--O--.
[0068] According to an embodiment, the present disclosure relates
to a compound of Formula I or its stereoisomers, pharmaceutically
acceptable salts, complexes, hydrates, solvates, tautomers,
polymorphs, racemic mixtures, optically active forms and
pharmaceutically active derivative thereof, wherein, n is 1.
[0069] According to an embodiment, the present disclosure relates
to a compound of Formula I or its stereoisomers, pharmaceutically
acceptable salts, complexes, hydrates, solvates, tautomers,
polymorphs, racemic mixtures, optically active forms and
pharmaceutically active derivative thereof, which is selected from
a group consisting of: [0070] 1)
.+-.Ethyl-2-(-7-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-2,3,5,7-tetrahy-
drobenzo[5,6]oxepino[4,3-c]pyridin-5-yl)acetate [0071] 1A) Ethyl
2-((5S,7R)-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-2,3,5,7-tetrahydrobe-
nzo[5,6]oxepino[4,3-c]pyridin-5-yl)acetate [0072] 1B) Ethyl
2-((5S,7S)-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-2,3,5,7-tetrahydrobe-
nzo[5,6]oxepino[4,3-c]pyridin-5-yl)acetate [0073] 1C) Ethyl
2-((5R,7S)-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-2,3,5,7-tetrahydrobe-
nzo[5,6]oxepino[4,3-c]pyridin-5-yl)acetate [0074] 1D) Ethyl
2-((5R,7R)-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-2,3,5,7-tetrahydrobe-
nzo[5,6]oxepino[4,3-c]pyridin-5-yl)acetate [0075] 2)
.+-.Ethyl-2-(7-cyclohexyl-9-methoxy-2-methyl-3-oxo-2,3,5,7-tetrahydrobenz-
o[5,6]oxepino[4,3-c]pyridin-5-yl)acetate [0076] 3)
.+-.Ethyl-2-(7-(cyclopropylmethyl)-9-methoxy-2-methyl-3-oxo-2,3,5,7-tetra-
hydrobenzo[5,6]oxepino[4,3-c]pyridin-5-yl)acetate [0077] 4)
.+-.Ethyl-2-(9-methoxy-2-methyl-7-(5-methylpyridin-2-yl)-3-oxo-2,3,5,7-te-
trahydrobenzo[5,6]oxepino[4,3-c]pyridin-5-yl)acetate [0078] 5)
.+-.Ethyl-2-(7-(4-chlorophenyl)-9-fluoro-2-methyl-3-oxo-2,3,5,7-tetrahydr-
obenzo[5,6]oxepino[4,3-c]pyridin-5-yl)acetate [0079] 6)
.+-.Ethyl-2-(7-(4-chlorophenyl)-2-methyl-3-oxo-9-(trifluoromethyl)-2,3,5,-
7-tetrahydrobenzo[5,6]oxepino[4,3-c]pyridin-5-yl)acetate [0080] 7)
.+-.7-(4-chlorophenyl)-5-(2-hydroxyethyl)-9-methoxy-2-methyl-5,7-dihydrob-
enzo[5,6]oxepino[4,3-c]pyridin-3(2H)-one [0081] 8)
.+-.2-(-7-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-2,3,5,7-tetrahydroben-
zo[5,6]oxepino[4,3-c]pyridin-5-yl)-N-ethylacetamide [0082] 8A)
.+-.2-((5S,7R)-7-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-2,3,5,7-tetrah-
ydrobenzo[5,6]oxepino[4,3-c]pyridin-5-yl)-N-ethylacetamide [0083]
8B)
.+-.2-((5S,7S)-7-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-2,3,5,7-tetrah-
ydrobenzo[5,6]oxepino[4,3-c]pyridin-5-yl)-N-ethylacetamide [0084]
8C)
2-((5S,7R)-7-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-2,3,5,7-tetrahydro-
benzo[5,6]oxepino[4,3-c]pyridin-5-yl)-N-ethylacetamide [0085] 8D)
2-((5S,7S)-7-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-2,3,5,7-tetrahydro-
benzo[5,6]oxepino[4,3-c]pyridin-5-yl)-N-ethylacetamide [0086] 8E)
2-((5R,7S)-7-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-2,3,5,7-tetrahydro-
benzo[5,6]oxepino[4,3-c]pyridin-5-yl)-N-ethylacetamide [0087] 8F)
2-((5R,7R)-7-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-2,3,5,7-tetrahydro-
benzo[5,6]oxepino[4,3-c]pyridin-5-yl)-N-ethylacetamide [0088] 9)
.+-.2-(7-cyclohexyl-9-methoxy-2-methyl-3-oxo-2,3,5,7-tetrahydrobenzo[5,6]-
oxepino[4,3-c]pyridin-5-yl)-N-ethylacetamide [0089] 9A)
.+-.2-((5S,7R)-7-cyclohexyl-9-methoxy-2-methyl-3-oxo-2,3,5,7-tetrahydrobe-
nzo[5,6]oxepino[4,3-c]pyridin-5-yl)-N-ethylacetamide [0090] 9B)
.+-.2-((5S,7S)-7-cyclohexyl-9-methoxy-2-methyl-3-oxo-2,3,5,7-tetrahydrobe-
nzo[5,6]oxepino[4,3-c]pyridin-5-yl)-N-ethylacetamide [0091] 10)
.+-.2-(7-(cyclopropylmethyl)-9-methoxy-2-methyl-3-oxo-2,3,5,7-tetrahydrob-
enzo[5,6]oxepino[4,3-c]pyridin-5-yl)-N-ethylacetamide [0092] 10A)
.+-.2-((5S,7R)-7-(cyclopropylmethyl)-9-methoxy-2-methyl-3-oxo-2,3,5,7-tet-
rahydrobenzo[5,6]oxepino[4,3-c]pyridin-5-yl)-N-ethylacetamide
[0093] 10B)
.+-.2-((5S,7S)-7-(cyclopropylmethyl)-9-methoxy-2-methyl-3-oxo-2,3,5,7-tet-
rahydrobenzo[5,6]oxepino[4,3-c]pyridin-5-yl)-N-ethylacetamide
[0094] 11)
.+-.2-(9-methoxy-2-methyl-7-(5-methylpyridin-2-yl)-3-oxo-2,3,5,7-tetrahyd-
robenzo[5,6]oxepino[4,3-c]pyridin-5-yl)-N-ethylacetamide [0095]
11A)
.+-.2-((5S,7S)-9-methoxy-2-methyl-7-(5-methylpyridin-2-yl)-3-oxo-2,3,5,7--
tetrahydrobenzo[5,6]oxepino[4,3-c]pyridin-5-yl)-N-ethylacetamide
[0096] 11B)
.+-.2-((5S,7R)-9-methoxy-2-methyl-7-(5-methylpyridin-2-yl)-3-oxo-2,3-
,5,7-tetrahydrobenzo[5,6]oxepino[4,3-c]pyridin-5-yl)-N-ethylacetamide
[0097] 12)
.+-.2-(7-(4-chlorophenyl)-9-fluoro-2-methyl-3-oxo-2,3,5,7-tetrahydrobenzo-
[5,6]oxepino[4,3-c]pyridin-5-yl)-N-ethylacetamide [0098] 12A)
.+-.2-((5S,7R)-9-fluoro-2-methyl-3-oxo-7-phenyl-2,3,5,7-tetrahydrobenzo[5-
,6]oxepino[4,3-c]pyridin-5-yl)-N-ethylacetamide [0099] 12B)
.+-.2-((5S,7S)-9-fluoro-2-methyl-3-oxo-7-phenyl-2,3,5,7-tetrahydrobenzo[5-
,6]oxepino[4,3-c]pyridin-5-yl)-N-ethylacetamide [0100] 13)
.+-.2-(7-(4-chlorophenyl)-2-methyl-3-oxo-9-(trifluoromethyl)-2,3,5,7-tetr-
ahydrobenzo[5,6]oxepino[4,3-c]pyridin-5-yl)-N-ethylacetamide [0101]
13A)
.+-.2-((5S,7R)-2-methyl-3-oxo-7-phenyl-9-(trifluoromethyl)-2,3,5,7-tetrah-
ydrobenzo[5,6]oxepino[4,3-c]pyridin-5-yl)-N-ethylacetamide [0102]
13B)
.+-.2-((5S,7S)-2-methyl-3-oxo-7-phenyl-9-(trifluoromethyl)-2,3,5,7-tetrah-
ydrobenzo[5,6]oxepino[4,3-c]pyridin-5-yl)-N-ethylacetamide [0103]
14)
.+-.Ethyl-2-(7-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-b-
enzo[c]pyrido[3,4-e]azepin-5-yl)acetate [0104] 15) .+-.Ethyl
2-(7-cyclohexyl-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c]pyrido[3,-
4-e]azepin-5-yl)acetate [0105] 16)
.+-.Ethyl-2-(9-methoxy-2-methyl-3-oxo-7-(pyridin-2-yl)-3,5-dihydro-2H-ben-
zo[c]pyrido[3,4-e]azepin-5-yl)acetate [0106] 17)
.+-.Ethyl-2-(7-(cyclopropylmethyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2-
H-benzo[c]pyrido[3,4-e]azepin-5-yl)acetate [0107] 18)
.+-.Ethyl-2-(9-methoxy-2-methyl-3-oxo-7-(trifluoromethyl)-3,5-dihydro-2H--
benzo[c]pyrido[3,4-e]azepin-5-yl)acetate [0108] 19)
.+-.Ethyl-2-(9-methoxy-2,7-dimethyl-3-oxo-3,5-dihydro-2H-benzo[c]pyrido[3-
,4-e]azepin-5-yl)acetate [0109] 20)
.+-.Ethyl-2-(9-methoxy-2-methyl-7-(5-methylpyridin-2-yl)-3-oxo-3,5-dihydr-
o-2H-benzo[c]pyrido[3,4-e]azepin-5-yl)acetate [0110] 21)
.+-.Ethyl-2-(7-(4-chlorophenyl)-2-isopropyl-9-methoxy-3-oxo-3,5-dihydro-2-
H-benzo[c]pyrido[3,4-e]azepin-5-yl)acetate [0111] 22)
.+-.Ethyl-2-(7-(4-chlorophenyl)-9-fluoro-2-methyl-3-oxo-3,5-dihydro-2H-be-
nzo[c]pyrido[3,4-e]azepin-5-yl)acetate [0112] 23)
.+-.Ethyl-2-(7-(2,6-difluorophenyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro--
2H-benzo[c]pyrido[3,4-e]azepin-5-yl)acetate [0113] 24)
.+-.Ethyl-2-(7-(4-chloro-2-methylphenyl)-9-methoxy-2-methyl-3-oxo-3,5-dih-
ydro-2H-benzo[c]pyrido[3,4-e]azepin-5-yl)acetate [0114] 25)
.+-.2-(7-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c-
]pyrido[3,4-e]azepin-5-yl)-N-ethylacetamide [0115] 25A)
(S)-2-(7-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c-
]pyrido[3,4-e]azepin-5-yl)-N-ethylacetamide. [0116] 25B)
(R)-2-(7-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c-
]pyrido[3,4-e]azepin-5-yl)-N-ethylacetamide. [0117] 26)
.+-.2-(7-cyclohexyl-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c]pyrid-
o[3,4-e]azepin-5-yl)-N-ethylacetamide [0118] 26A)
(S)-2-(7-cyclohexyl-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c]pyrid-
o[3,4-e]azepin-5-yl)-N-ethylacetamide [0119] 26B)
(R)-2-(7-cyclohexyl-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c]pyrid-
o[3,4-e]azepin-5-yl)-N-ethylacetamide [0120] 27)
.+-.2-(9-methoxy-2-methyl-3-oxo-7-(pyridin-2-yl)-3,5-dihydro-2H-benzo[c]p-
yrido[3,4-e]azepin-5-yl)-N-ethylacetamide [0121] 27A)
(S)-2-(9-methoxy-2-methyl-3-oxo-7-(pyridin-2-yl)-3,5-dihydro-2H-benzo[c]p-
yrido[3,4-e]azepin-5-yl)-N-ethylacetamide [0122] 27B)
(R)-2-(9-methoxy-2-methyl-3-oxo-7-(pyridin-2-yl)-3,5-dihydro-2H-benzo[c]p-
yrido[3,4-e]azepin-5-yl)-N-ethylacetamide [0123] 28)
.+-.2-(7-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c-
]pyrido[3,4-e]azepin-5-yl)acetamide [0124] 29)
.+-.2-(7-(4-chlorophenyl)-9-hydroxy-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c-
]pyrido[3,4-e]azepin-5-yl)-N-ethylacetamide [0125] 30)
.+-.2-(7-(cyclopropylmethyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-benz-
o[c]pyrido[3,4-e]azepin-5-yl)-N-ethylacetamide [0126] 30A)
(S)-2-(7-(cyclopropylmethyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-benz-
o[c]pyrido[3,4-e]azepin-5-yl)-N-ethylacetamide [0127] 30B)
(R)-2-(7-(cyclopropylmethyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-benz-
o[c]pyrido[3,4-e]azepin-5-yl)-N-ethylacetamide [0128] 31)
.+-.2-(7-(4-chlorophenyl)-9-(difluoromethoxy)-2-methyl-3-oxo-3,5-dihydro--
2H-benzo[c]pyrido[3,4-e]azepin-5-yl)-N-ethylacetamide [0129] 32)
.+-.2-(9-methoxy-2-methyl-3-oxo-7-(trifluoromethyl)-3,5-dihydro-2H-benzo[-
c]pyrido[3,4-e]azepin-5-yl)-N-ethylacetamide [0130] 32A)
(S)-2-(9-methoxy-2-methyl-3-oxo-7-(trifluoromethyl)-3,5-dihydro-2H-benzo[-
c]pyrido[3,4-e]azepin-5-yl)-N-ethylacetamide [0131] 32B)
(R)-2-(9-methoxy-2-methyl-3-oxo-7-(trifluoromethyl)-3,5-dihydro-2H-benzo[-
c]pyrido[3,4-e]azepin-5-yl)-N-ethylacetamide [0132] 33)
.+-.2-(7-(4-cyanophenyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c]-
pyrido[3,4-e]azepin-5-yl)-N-ethylacetamide [0133] 34)
.+-.2-(9-methoxy-2-methyl-7-(5-methylpyridin-2-yl)-3-oxo-3,5-dihydro-2H-b-
enzo[c]pyrido[3,4-e]azepin-5-yl)-N-ethylacetamide [0134] 35)
.+-.2-(7-(4-chlorophenyl)-2-methyl-3-oxo-9-(trifluoromethyl)-3,5-dihydro--
2H-benzo[c]pyrido[3,4-e]azepin-5-yl)-N-ethylacetamide [0135] 36)
.+-.2-(7-(4-chlorophenyl)-2-isopropyl-9-methoxy-3-oxo-3,5-dihydro-2H-benz-
o[c]pyrido[3,4-e]azepin-5-yl)-N-ethylacetamide [0136] 37)
.+-.2-(7-(4-chlorophenyl)-9-fluoro-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c]-
pyrido[3,4-e]azepin-5-yl)-N-ethylacetamide [0137] 38)
.+-.2-(7-(2,6-difluorophenyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-ben-
zo[c]pyrido[3,4-e]azepin-5-yl)-N-ethylacetamide [0138] 39)
.+-.2-(7-(4-chloro,2-methylphenyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2-
H-benzo[c]pyrido[3,4-e]azepin-5-yl)-N-ethylacetamide [0139] 40)
.+-.2-(7-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c-
]pyrido[3,4-e]azepin-5-yl)-N-(4-hydroxyphenyl)acetamide [0140] 40A)
(S)-2-(7-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c-
]pyrido[3,4-e]azepin-5-yl)-N-(4-hydroxyphenyl)acetamide [0141] 40B)
(R)-2-(7-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c-
]pyrido[3,4-e]azepin-5-yl)-N-(4-hydroxyphenyl)acetamide [0142] 41)
.+-.7-(4-chlorophenyl)-9-methoxy-2,5-dimethyl-2H-benzo[c]pyrido[3,4-e]aze-
pin-3(5H)-one [0143] 41A)
(S)-7-(4-chlorophenyl)-9-methoxy-2,5-dimethyl-2H-benzo[c]pyrido[3,4-e]aze-
pin-3(5H)-one [0144] 41B)
(R)-7-(4-chlorophenyl)-9-methoxy-2,5-dimethyl-2H-benzo[c]pyrido[3,4-e]aze-
pin-3(5H)-one [0145] 42)
.+-.7-(4-chlorophenyl)-9-methoxy-2-methyl-2H-benzo[c]pyrido[3,4-e]azepin--
3(5H)-one [0146] 43)
.+-.2-(7-(4-chlorophenyl)-2-methyl-3-oxo-9-(trifluoromethyl)-3,5-dihydro--
2H-benzo[c]pyrido[3,4-e]azepin-5-yl)acetic acid [0147] 44)
.+-.2-(7-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c-
]pyrido[3,4-e]azepin-5-yl)acetic acid [0148] 45)
.+-.tert-butyl((7-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2-
H-benzo[c]pyrido[3,4-e]azepin-5-yl)methyl)carbamate [0149] 46)
.+-.N-((7-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-benzo[-
c]pyrido[3,4-e]azepin-5-yl)methyl)acetamide
[0150] According to an embodiment, the present disclosure relates
to a process of preparation of compound of Formula I or its
stereoisomers, pharmaceutically acceptable salts, complexes,
hydrates, solvates, tautomers, polymorphs, racemic mixtures,
optically active forms and pharmaceutically active derivative
thereof.
[0151] According to an embodiment, the present disclosure relates
to a pharmaceutical composition including a compound of Formula
(I), or its stereoisomers, pharmaceutically acceptable salts,
complexes, hydrates, solvates, tautomers, polymorphs, racemic
mixtures, optically active forms and pharmaceutically active
derivative thereof, and at least one pharmaceutically acceptable
carrier, diluent, or excipient.
[0152] According to an embodiment, the present disclosure relates
to the use of a compound of Formula (I) or (Ia) and pharmaceutical
composition including a compound of Formula (I) or (Ia), or its
stereoisomers, pharmaceutically acceptable salts, complexes,
hydrates, solvates, tautomers, polymorphs, racemic mixtures,
optically active forms and pharmaceutically active derivative
thereof, in the manufacture of a medicament for the treatment
and/or prevention of diseases and/or disorders in which aberrant,
abnormal or deregulated activity of BET family of bromodomain
containing proteins; in particular BRD2, BRD3, BRD4 and BRDT
proteins.
[0153] According to an embodiment, the present disclosure relates
to the use of a compound of Formula (I) or (Ia) and pharmaceutical
composition including a compound of Formula (I) or (Ia) or its
stereoisomers, pharmaceutically acceptable salts, complexes,
hydrates, solvates, tautomers, polymorphs, racemic mixtures,
optically active forms and pharmaceutically active derivative
thereof, in the manufacture of a medicament for the production of
an anti-cancer effect in a warm-blooded animal such as man.
[0154] According to an embodiment, the present disclosure relates
to a method for treating a variety of diseases or conditions
related to systemic or tissue inflammation, inflammatory responses
to infection or hypoxia, cellular activation and proliferation,
lipid metabolism, fibrosis and in the prevention and treatment of
viral infections.
[0155] According to an embodiment, the present disclosure relates
to a method for treating cancer in patients including
administration of a therapeutically effective amount of a compound
of Formula (I).
[0156] According to an embodiment, the present disclosure relates
to a method for treating proliferative conditions or cancer,
comprising administering to a subject suffering from proliferative
conditions or cancer, a therapeutically effective amount of a
compound of Formula (I), in the presence or absence of other
clinically relevant cytotoxic agents or non-cytotoxic agents to a
mammal in need thereof.
[0157] According to an embodiment, the present disclosure relates
to a method for treating a disorder caused by, associated with or
accompanied by disruptions of cell proliferation and/or
angiogenesis and the subsequent metastasis including administration
of a therapeutically effective amount of a compound of Formula
(I).
[0158] According to an embodiment, the present disclosure relates
to a method for treating cancer in patient including administration
of effective amount of compounds of formula (I). The cancer can be
either a hematologic malignancy or solid tumor. Hematological
malignancy is selected from the group consisting of B-cell
lymphoma, T-cell lymphoma and leukemia. In the case of solid
tumors, the tumors are selected from the group consisting of breast
cancer, lung cancer, ovarian cancer, prostate cancer, head cancer,
neck cancer, renal cancer, gastric cancer, colon cancer, pancreatic
cancer and brain cancer.
[0159] According to an embodiment, the present disclosure relates
to a method for treating and/or preventing a neurodegenerative
disease or disorder comprising administering, to a patient in need
of treatment, a therapeutically effectively amount of a composition
comprising a compound of Formula I and a pharmaceutically
acceptable carrier.
[0160] In one aspect of this embodiment, the invention provides a
compound of Formula I for use in treating and/or preventing a
neurodegenerative disorder or condition. In a related aspect, the
invention provides for the use of a compound of Formula I for the
manufacture of a medicament for treating and/or preventing a
neurodegenerative disorder or condition.
[0161] According to an embodiment, the present disclosure relates
to the compounds of Formula (I) useful for treating proliferative
diseases. A proliferative disease includes, for example, a tumor
disease and/or metastates.
[0162] According to an embodiment, the compounds of the present
disclosure are useful for treating a proliferative disease that is
refractory to the treatment with other chemotherapeutics; or a
tumor that is refractory to treatment with other therapeutics due
to multidrug resistance.
[0163] According to an embodiment, the present disclosure relates
to a method of treatment of cancer, said method comprising
administering a combination of the compound or the pharmaceutical
composition with other clinically relevant immune modulators agents
to a mammal in need of thereof.
[0164] According to an embodiment, the compounds of the present
invention are able to slow tumor growth, stop tumor growth or bring
about the regression of tumors and to prevent the formation of
tumor metastasis (including micrometastatis) and the growth of
metastates (including micrometastatis). In addition they can be
used in epidermal hyper proliferation.
[0165] The compound of formula I of the present invention can be
used as a prophylactic or therapeutic agent for cancer. Examples of
the cancer not restricted include breast cancer, prostate cancer,
pancreatic cancer, gastric cancer, lung cancer, colon cancer,
rectal cancer, esophagus cancer, duodenal cancer, tongue cancer,
pharyngeal cancer, brain tumor, neurinoma, non-small cell lung
cancer, small cell lung cancer, liver cancer, kidney cancer, bile
duct cancer, uterine body cancer, cervical cancer, ovarian cancer,
urinary bladder, skin cancer, hemangioma, malignant lymphoma,
malignant melanoma, thyroid cancer, bone tumor, vascular fibroma,
retinoblastoma, penile cancer, pediatric solid cancer, lymphoma,
myeloma and leukemia (including, for example acute myelogenous
leukemia (AML), chronic myelogenous leukemia (CML), chronic
neutrophilic leukemia, chronic eosinophilic leukemia, chronic
lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL) or
hariy cell leukemia).
[0166] The compound of formula I of the present invention can be
used as a prophylactic or therapeutic agent for various chronic
autoimmune and inflammatory conditions such as rheumatoid
arthritis, osteoarthritis, acute gout, psoriasis, systemic lupus
erythematosus, multiple sclerosis, inflammatory bowel disease
(Crohn's disease and Ulcerative colitis), asthma, chronic
obstructive airways disease, pneumonitis, myocarditis,
pericarditis, myositis, eczema, dermatitis, alopecia, vitiligo,
bullous skin diseases, nephritis, vasculitis, atherosclerosis,
Alzheimer's disease, depression, retinitis, uveitis, scleritis,
hepatitis, pancreatitis, primary biliary cirrhosis, sclerosing
cholangitis, Addison's disease, hypophysitis, thyroiditis, type I
diabetes and acute rejection of transplanted organs.
[0167] In one embodiment, the invention provides a method of
inhibiting bromodomain activity comprising administering, to a
patient in need of treatment, an amount of a composition comprising
a compound of Formula I and a pharmaceutically acceptable carrier
sufficient to inhibit bromodomain activity.
[0168] In one aspect of this embodiment, the invention provides a
compound of Formula I for use in inhibiting bromodomain. In a
related aspect, the invention provides for the use of a compound of
Formula I for the manufacture of a medicament for inhibiting
bromodomain.
[0169] In one embodiment, the invention provides a method of
treating and/or preventing a neurodegenerative disease or disorder
comprising administering, to a patient in need of treatment, a
therapeutically effectively amount of a composition comprising a
compound of Formula I and a pharmaceutically acceptable carrier. In
one aspect of this embodiment, the invention provides a compound of
Formula I for use in treating and/or preventing a neurodegenerative
disorder or condition. In a related aspect, the invention provides
for the use of a compound of Formula I for the manufacture of a
medicament for treating and/or preventing a neurodegenerative
disorder or condition.
[0170] In another aspect, the compound may be administered in
combination therapy by combining the compound of formula (I) with
one or more separate agents, not limited to targets such as DNA
methyltransferase, heat shock proteins (e.g. HSP90) kinases and
other matrix metalloproteinases.
[0171] "Combination therapy" includes the administration of the
subject compounds in further combination with other biologically
active ingredients (such as vinblastine, afatinib, nilotinib,
vemarafinib, aflibercept, axitinib, dasatinib, sorafenib,
bosutinib, crizotinib, but are not limited to, different
antineoplastic agent) and non-drug therapies (such as, but are not
limited to, surgery or radiation treatment). The compounds
described herein can be used in combination with other
pharmaceutically active compounds, preferably, which will enhance
the effect of the compounds of the invention. The compounds can be
administered simultaneously or sequentially to the other drug
therapy.
[0172] In another aspect, the subject compounds may be combined
with the antineoplastic agents (e.g. small molecules, monoclonal
antibodies, antisense RNA and fusion proteins) that inhibit one or
more biological targets. Such combination may enhance therapeutic
efficacy over the efficacy achieved by any of the agents alone and
may prevent or delay the appearance of resistant variants.
[0173] In another aspect, the subject compounds may be combined
with immunoncology drugs not restricting to PDL-1 inhibitor, IDO,
TDO, CTLA4 or any other drugs which is involved in the immune
modulation.
[0174] A term once described, the same meaning applies for it,
throughout the patent.
Scheme:
[0175] According to an embodiment, the present disclosure relates
to a process as shown in the following scheme-1, for the
preparation of compounds of the Formula (I), wherein all the groups
are as defined earlier.
##STR00010##
[0176] The said process for the preparation of the compounds of
formula (I) comprises of the following:
The compound 1 was converted to compound 2 under standard
conditions either using malonic acid or witting reagent. Compound 2
was treated with intermediate 3 in the presence of Pd catalyst C--C
bond formation under standard conditions to obtained 4.
[0177] Compound 4 under standard carbonyl reductions using sodium
borohydride or sodium cyanoborohydride or like to give the
corresponding alcohol 5. Intramolecular cyclization of 5 using
bases such as inorganic or organic bases gives 6. Further
exploration of 6 gives compound of formula 1. Treating compound 4
with ammonium formate or ammonium acetate or the like in polar
protic solvent such as methanol, ethanol or the like gives 7.
Further exploration of 7 gives compound of formula 1. Compound 1
can be converted to compound 8 by treating corresponding
sulfoximine. Compound 8 when treated with appropriately substituted
Grignard reagent in the presence of suitable solvents such as
tetrahydrofuran or dioxane or diethylether gave compound 9.
Compound 9 on treatment with acids such as HCl, H.sub.2SO.sub.4 and
the like gave compound of formula 1. Where in R.sup.1, R.sup.2,
R.sup.3, R.sup.4 and Z are described above. The examples given
below are provided by the way of illustration only and therefore
should not be construed to limit the scope of the invention.
EXAMPLES
[0178] The following examples provide the details about the
synthesis, activities, and applications of the compounds of the
present disclosure. It should be understood the following is
representative only, and that the invention is not limited by the
details set forth in these examples.
Example 1
.+-.Ethyl
2-(-7-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-2,3,5,7-tetrahyd-
robenzo[5,6]oxepino[4,3-c]pyridin-5-yl)acetate
##STR00011##
[0179] Step A: methyl
5-bromo-2-oxo-1,2-dihydropyridine-4-carboxylate-II
[0180] To a stirred solution of Conc.H.sub.2SO.sub.4 (50 mL, 0.668
mol) in water (500 mL) was added methyl
2-amino-5-bromoisonicotinate (I, 50 g, 0.226 mol). The resulting
clear brown solution was cooled to 0.degree. C. To the mixture was
added NaNO.sub.2 (50 g, 0.668 mmol) in water (150 mL) drop wise
using addition funnel at 0.degree. C. Vigorous effervescence with
evolution of N.sub.2 gas was observed. The reaction mixture was
warmed to room temperature. The reaction mixture was stirred for
additional 30 min at room temperature. The solid was filtered,
washed with water (3.times.150 mL) followed by n-hexane
(2.times.100 mL) to yield as a yellow solid. (48.0 g, 93% yield).
.sup.1H NMR (DMSO-d.sub.6, 400 MHz), .delta. (ppm): 7.62 (s, 1H),
6.90 (s, 1H), 5.0 (br, 1H), 3.98 (s, 3H). MS (ESI): mass calcd. for
C.sub.7H.sub.7BrN.sub.2O.sub.2, 232.01; m/z found,
234[M+2H].sup.+.
Step B: methyl
5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxylate-III
[0181] To a stirred solution of methyl
5-bromo-2-oxo-1,2-dihydropyridine-4-carboxylate (II, 25.0 g, 0.107
mol) in acetonitrile (500 mL) was added cesium carbonate (42 g,
0.129 mol) at 5-10.degree. C. To this mixture was added methyl
iodide (7.4 mL, 0.118 mol). The reaction mixture was warmed to room
temperature and stirred for 4 h. The reaction mixture was filtered
and concentrated to get the product as a brown solid. (25 g, 95%
yield), .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta. (ppm): 8.18
(s, 1H), 6.70 (s, 1H), 3.83 (s, 3H), 3.42 (s, 3H). MS (ESI): mass
calcd. for C.sub.8H.sub.8BrNO.sub.3, 246.01; m/z found,
248[M+2H].sup.+.
Step C: 5-bromo-4-(hydroxymethyl)-1-methylpyridin-2(1H)-one-IV
[0182] To the 5-bromo-4-(hydroxymethyl)-1-methylpyridin-2(1H)-one
(III, 24.0 g, 0.096 mol) was added THF (250 mL), DME (250 mL) and
NaBH.sub.4 (10 g, 0.213 mol) at room temperature. The reaction
mixture was heated to 75-80.degree. C. To the reaction mixture was
added slowly MeOH (250 mL) using additional funnel. The reaction
mixture was stirred at 70-75.degree. C. for 1h. The reaction
mixture was concentrated under reduced pressure. The concentrate
was triturated with 50 mL of water and filtered to yield as a pale
yellowish solid. (15.0 g, 71% yield), .sup.1H NMR (DMSO-d.sub.6,
400 MHz): .delta. (ppm): 7.98 (s, 1H), 6.44 (s, 1H), 5.56 (br, 1H),
4.29 (s, 2H), 3.38 (s, 3H). MS (ESI): mass calcd. for
C.sub.7H.sub.8BrNO.sub.2, 218.05; m/z found, 220 [M+2H].sup.+.
Step D:
5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-4-carbaldehyde-V
[0183] To the 5-bromo-4-(hydroxymethyl)-1-methylpyridin-2(1H)-one.
(IV, 20.0 g, 0.091 mol) was added acetonitrile (2 L) and stirred at
room temperature for 30 mins to get a slightly turbid mixture. To
this mixture, Dess-martin-periodinane reagent (60 g, 0.137 mol) was
added at room temperature. The resulting turbid milky suspension
was stirred at room temperature for 3 h. To the reaction mixture
was added saturated sodium bicarbonate aqueous solution (50 mL) and
stirred for 15 min. The reaction mixture was filtered over celite
bed. The celite bed was washed with 100 mL of acetonitrile. The
acetonitrile organic layer was concentrated 1/3.sup.rd portion to
get a turbid mixture again. The turbid mixture was filtered over
celite bed once again and washed with 100 mL of acetonitrile. The
acetonitrile organic layer was concentrated to dryness. The residue
was dissolved in 5% MeOH in DCM (250 mL) and washed with 50 mL of
water. The organic layer was concentrated to get the title compound
5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-4-carbaldehyde as a semi
solid (12.3 g, 62% yield), .sup.1H NMR (DMSO-d.sub.6, 400 MHz):
.delta. (ppm): 9.94 (s, 1H), 8.23 (s, 1H), 6.81 (s, 1H), 3.45 (s,
3H). MS (ESI): mass calcd. for C.sub.7H.sub.6BrNO.sub.2, 216.03;
m/z found, 218[M+2H].sup.+.
Step E: (E)-ethyl
3-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)acrylate-VI
[0184] To a suspension of NaH (2.6 g, 0.064 mol) in dry THF (100
mL) at 0.degree. C. was added portion wise triethylphosphonoacetate
(12 mL, 0.06 mol) under nitrogen atmosphere. The reaction mixture
was stirred for 30 min at 0.degree. C. to get a clear solution. To
the mixture,
5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-4-carbaldehyde (V, 10 g,
0.046 mol) in DMSO (50 mL) was added under inert atmosphere. The
reaction mixture was warmed to room temperature and stirred for 1h.
The reaction mixture was quenched with aq. NH.sub.4Cl solution (20
mL), extracted with EtOAc (100 mL x 2 times). The combined organic
layer was washed with ice cold water 100 mL. The organic layer was
dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated
to get a semi solid. This semi solid was washed with 2.times.50 mL
of n-pentane to yield as a yellow solid. (9 g, 68% yield), .sup.1H
NMR (DMSO-d.sub.6, 400 MHz): .delta. (ppm): 8.15 (s, 1H), 7.49-7.53
(d, J=16 Hz, 1H), 6.89 (s, 1H), 6.68-6.72 (d, J=16 Hz, 1H), 3.41
(s, 3H), 4.18-4.23 (q, J=7.2 Hz, 2H), 1.23-1.26 (t, J=6.8 Hz, 3H).
MS (ESI): mass calcd. for C.sub.11H.sub.12BrNO.sub.3, 286.12; m/z
found, 288[M+2H].sup.+.
Synthesis of Intermediate VII
##STR00012##
[0185] Step J:
2-bromo-.alpha.-(4-chlorophenyl)-5-methoxy-benzenemethanol-VIIC
[0186] To a stirred solution of 2-bromo-5-methoxybenzaldehyde
(VIIA, 25 g, 116 mmol) in dry tetrahydrofuran (350 mL) under
N.sub.2 atmosphere at 0.degree. C., 4-chlorophenylmagnesium bromide
1.0 M solution in diethyl ether (140 mL, 140 mmol) was added drop
wise. Then reaction mixture was left for stirring over 2 h. After
the completion of reaction, reaction mixture was quenched by
saturated ammonium chloride solution and diluted with ethyl
acetate. Reaction mixture was filtered through celite bed. Organic
layer was separated and washed with brine, dried over sodium
sulphate, concentrated under reduced pressure. The Crude was washed
with n-pentane to yield as a off white solid (38 g, 95% yield). MS
(ESI): mass calcd for C.sub.14H.sub.12BrClO.sub.2, 327.60; m/z
found, 326[M-H].sup.-.
Step I:
(2-bromo-5-methoxyphenyl)(4-chlorophenyl)-Methanone-VIID
[0187] To a stirred solution of
2-bromo-.alpha.-(4-chlorophenyl)-5-methoxy-Benzenemethanol (VIIC,
20 g, 0.06 mol) in dry dichloromethane (350 mL), pyridinium
chlorochromate (17 g, 0.078 mol) was added under N.sub.2
atmosphere. The reaction mixture was stirred for 1.5 h. After the
completion of reaction, mixture was filtered through silica gel
(100-200 mesh) bed. Then dichloromethane layer was washed by
saturated sodium bicarbonate solution, followed by brine, dried
over sodium sulphate. Organic layer was concentrated and purified
using silica gel column chromatography using 2-5% EtOAc/hexane as
the eluent to yield as a white solid (13 g, 65% yield). MS (ESI):
mass calcd for C.sub.14H.sub.10BrClO.sub.2, 325.59; m/z found,
326[M+H].sup.+.
[0188] Step K:
(4-chlorophenyl)[5-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl-
)phenyl]Methanone-VII
[0189] To a stirred solution of
(2-bromo-5-methoxyphenyl)(4-chlorophenyl)-Methanone (VIID, 14.8 g,
0.045 mol) in dioxane (350 mL), potassium acetate (26.7 g, 0.27
mol) and Bis(pinacolato)diborane (18 g, 0.0726 mol) were added. The
mixture was purged with nitrogen gas for 30 min. Then
Pd(dppf)Cl.sub.2 (2.2 g, 0.0027 mol) was added. The reaction
mixture was refluxed at 95.degree. C. for 2.5 h. After the
completion of reaction, reaction mixture was filtered through
celite bed. Then dioxane was completely evaporated. Crude was
dissolved in ethyl acetate, washed with brine, dried over sodium
sulphate, concentrated. The crude was purified by Biotage purifier,
eluted in 1%-3% EA/Hexane to yield as a white solid (10 g, 59%
yield). MS (ESI): mass calcd for C.sub.20H.sub.22BClO.sub.4,
372.65; m/z found, 373[M+H].sup.+.
Step F: (E)-ethyl
3-(5-(2-(4-chlorobenzoyl)-4-methoxyphenyl)-1-methyl-2-oxo-1,2-dihydropyri-
din-4-yl)acrylate-VIII
[0190] To a stirred solution of (E)-ethyl
3-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)acrylate (VI, 2.0
g, 6.99 mmol) in dimethoxy ethane/water (60:15 mL),
(4-chlorophenyl)(5-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2
yl)phenyl)methanone (VII, 3.38 g, 9.08 mmol), sodium carbonate (2.2
mL, 20.97 mmol) was added at room temperature and purged with
nitrogen gas for 15 min, followed by Pd(PPh.sub.3).sub.4(0.8 g,
0.699 mmol) was added under nitrogen atmosphere. The mixture was
stirred for 28 h at 90.degree. C. The reaction mixture was cooled
to room temperature and concentrated the mixture under reduced
pressure. The crude product was dissolved in ethyl acetate. The
organic layer was washed with brine, dried over Na.sub.2SO.sub.4,
concentrated under reduced pressure. The crude was purified by
combiflash (Silica gel, 5-80% EtOAc/hexane) to give yellow solid
(1.25 g, 40% yield). .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta.
(ppm): 9.13 (s, 1H), 8.07 (s, 1H), 7.63-7.61 (d, J=8.0 Hz, 2H),
7.52-7.50 (d, J=8.0 Hz, 2H), 4.47 (m, 1H), 4.31 (m, 1H), 4.05 (m,
3H), 3.78 (m, 1H), 3.02 (m, 1H), 2.74 (m, 1H), 2.31 (m, 1H),
1.77-1.68 (m, 1H), 1.35 (t, J=4 Hz, 2H), 1.13 (s, 2H), 0.99 (t, J=8
Hz, 2H). MS (ESI): mass calcd. for C.sub.25H.sub.22ClNO.sub.5,
451.9; m/z found, 452.1[M+H].sup.+.
[0191] Step G: (E)-ethyl
3-(5-(2-((4-chlorophenyl)(hydroxy)methyl)-4-methoxyphenyl)-1-methyl-2-oxo-
-1,2-dihydropyridin-4-yl)acrylate-IX
[0192] To a stirred solution of (E)-ethyl
3-(5-(2-(4-chlorobenzoyl)-4-methoxyphenyl)-1-methyl-2-oxo-1,2-dihydropyri-
din-4-yl)acrylate (1.25 g, 2.76 mmol) in methanol (30 mL), sodium
borohydride (0.153 g, 4.14 mmol) was added at room temperature
under nitrogen atmosphere. The reaction mixture was stirred for 1h
at room temperature. The reaction was monitored by TLC, after
completion of the reaction; mixture was quenched with saturated
ammonium chloride and concentrated under reduced pressure. The
residue was partitioned with ethyl acetate and water. The organic
layer was washed with brine, dried over Na.sub.2SO.sub.4,
concentrated under reduced pressure to yield a yellow solid (1.25 g
crude). MS (ESI): mass calcd. for C.sub.25H.sub.24ClNO.sub.5,
453.91; m/z found, 454.1[M+H].sup.+.
Step H: .+-.ethyl
2-((7-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-2,3,5,7-tetrahydrobenzo[5-
,6]oxepino[4,3-c]pyridin-5-yl)acetate--Example 1
##STR00013##
[0194] To a stirred solution of (E)-ethyl
3-(5-(2-((4-chlorophenyl)(hydroxy)methyl)-4-methoxyphenyl)-1-methyl-2-oxo-
-1,2-dihydropyridin-4-yl)acrylate (0.15 g, 0.33 mmol) in ethanol
(10 mL), potassium carbonate (0.068 g, 0.495 mmol) was added at
room temperature under nitrogen atmosphere. The mixture was stirred
for 24 h at room temperature. After completion of the reaction, the
mixture was quenched with water and concentrated under reduced
pressure. The residue was partitioned with ethyl acetate and water.
The organic layer was washed with brine, dried over
Na.sub.2SO.sub.4, concentrated under reduced pressure. The crude
was purified by HPLC using Inertsil ODS (250 mm .times.4.6 mm
.times.5.mu.) column with 0.01% ammonia/water and acetonitrile as
mobile phase to yield two diastereomers as white solid (0.05 g,
33.3% yield). MS (ESI): mass calcd. for C.sub.25H.sub.24ClNO.sub.5,
453.91; m/z found, 454.2[M+H].sup.+.
[0195] Preparative Chiral HPLC Method for the Separation of
Diastereomers 1
Column: CHIRALPAK IA (250 mm .times.4.6 mm.times.5 .mu.m)
Wavelength: 254 nm UV
[0196] Injection Volume: 25.0 .mu.l/min 20 deg C.
Eluent: 80:20:0.1 MTBE:MeOH:DEA
Example 1A
Ethyl-2-((5S,7R)-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-2,3,5,7-tetrahy-
drobenzo[5,6]oxepino[4,3-c]pyridin-5-yl)acetate
##STR00014##
[0198] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta. (ppm) 7.8 (s,
1H), 7.38 (d, J=8.4 Hz, 1H), 7.25 (d, J=8.4 Hz, 2H), 7.08 (d, J=8.4
Hz, 2H), 7.03-7.00 (dd, J=14.0 Hz, J=2.0 Hz, 1H), 6.81 (bs, 1H),
6.35 (s, 1H), 5.95 (s, 1H), 4.88 (t, J=8.4 Hz, 1H), 4.09-4.04 (m,
2H). 3.75 (s, 3H), 3.4 (s, 3H), 2.80-2.78 (m, 2H), 1.16 (t, J=7.2
Hz, 3H). MS (ESI): mass calcd. for C.sub.25H.sub.24ClNO.sub.5,
453.13; m/z found, 454.2[M+H].sup.+.
Example 1B
Ethyl-2-((5S,7S)-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-2,3,5,7-tetrahy-
drobenzo[5,6]oxepino[4,3-c]pyridin-5-yl)acetate
##STR00015##
[0200] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta. (ppm) 7.98 (s,
1H), 7.45 (d, J=8.4 Hz, 3H), 7.31 (d, J=8.0 Hz, 2H), 7.07-7.04 (dd,
J=2.4 Hz, J=2.4 Hz, 1H), 6.43 (s, 1H), 5.96-5.96 (d, J=1.6 Hz, 1H),
5.48 (s, 1H), 4.51 (m, 1H), 4.09-4.07 (m, 2H). 3.63 (s, 3H), 3.53
(s, 3H), 2.95 (d, J=7.2 Hz, 2H), 1.16 (t, J=7.2 Hz, 3H). MS (ESI):
mass calcd. for C.sub.25H.sub.24ClNO.sub.5, 453.13; m/z found,
454.2[M+H].sup.+.
Example 1C
Ethyl-2-((5R,7S)-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-2,3,5,7-tetrahy-
drobenzo[5,6]oxepino[4,3-c]pyridin-5-yl)acetate
##STR00016##
[0202] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta. (ppm) 7.8 (s,
1H), 7.38 (d, J=8.4 Hz, 1H), 7.25 (d, J=8.4 Hz, 2H), 7.08 (d, J=8.4
Hz, 2H), 7.03-7.00 (dd, J=14.0 Hz, J=2.0 Hz, 1H), 6.81 (bs, 1H),
6.35 (s, 1H), 5.95 (s, 1H), 4.88 (t, J=8.4 Hz, 1H), 4.09-4.04 (m,
2H). 3.75 (s, 3H), 3.4 (s, 3H), 2.80-2.78 (m, 2H), 1.16 (t, J=7.2
Hz, 3H). MS (ESI): mass calcd. for C.sub.25H.sub.24ClNO.sub.5,
453.13; m/z found, 454.2[M+H].sup.+.
Example 1D
Ethyl-2-((5R,7R)-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-2,3,5,7-tetrahy-
drobenzo[5,6]oxepino[4,3-c]pyridin-5-yl)acetate
##STR00017##
[0204] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta. (ppm) 7.98 (s,
1H), 7.45 (d, J=8.4 Hz, 3H), 7.31 (d, J=8.0 Hz, 2H), 7.07-7.04 (dd,
J=2.4 Hz, J=2.4 Hz, 1H), 6.43 (s, 1H), 5.96-5.96 (d, J=1.6 Hz, 1H),
5.48 (s, 1H), 4.51 (m, 1H), 4.09-4.07 (m, 2H). 3.63 (s, 3H), 3.53
(s, 3H), 2.95 (d, J=7.2 Hz, 2H), 1.16 (t, J=7.2 Hz, 3H). MS (ESI):
mass calcd. for C.sub.25H.sub.24ClNO.sub.5, 453.13; m/z found,
454.2[M+H].sup.+.
[0205] Following compounds were synthesized using the above
procedure as exemplified in example 1
Example 2
.+-.Ethyl-2-(7-cyclohexyl-9-methoxy-2-methyl-3-oxo-2,3,5,7-tetrahydrobenzo-
[5,6]oxepino[4,3-c]pyridin-5-yl)acetate
##STR00018##
[0207] MS (ESI): mass calcd. for C.sub.25H.sub.31NO.sub.5, 425.1;
m/z found, 426.2[M+H].sup.+.
Example 3
.+-.Ethyl-2-(7-(cyclopropylmethyl)-9-methoxy-2-methyl-3-oxo-2,3,5,7-tetrah-
ydrobenzo[5,6]oxepino[4,3-c]pyridin-5-yl)acetate
##STR00019##
[0209] MS (ESI): mass calcd. for C.sub.23H.sub.27NO.sub.5, 397.2;
m/z found, 398.2 [M+H].sup.+.
Example 4
.+-.Ethyl-2-(9-methoxy-2-methyl-7-(5-methylpyridin-2-yl)-3-oxo-2,3,5,7-tet-
rahydrobenzo[5,6]oxepino[4,3-c]pyridin-5-yl)acetate
##STR00020##
[0211] MS (ESI): mass calcd. for C.sub.25H.sub.26N.sub.2O.sub.5,
434.2; m/z found, 435.2[M+H].sup.+.
Example 5
.+-.Ethyl-2-(7-(4-chlorophenyl)-9-fluoro-2-methyl-3-oxo-2,3,5,7-tetrahydro-
benzo[5,6]oxepino[4,3-c]pyridin-5-yl)acetate
##STR00021##
[0213] (ESI): mass calcd for C.sub.24H.sub.21ClFNO.sub.4, 441.2;
m/z found, 442.2 [M+H].sup.+.
Example 6
.+-.Ethyl-2-(7-(4-chlorophenyl)-2-methyl-3-oxo-9-(trifluoromethyl)-2,3,5,7-
-tetrahydrobenzo[5,6]oxepino[4,3-c]pyridin-5-yl)acetate
##STR00022##
[0215] (ESI): mass calcd for C.sub.25H.sub.21ClF.sub.3NO.sub.4,
491.3; m/z found, 492.3 [M+H].sup.+.
Example 7
.+-.7(4-chlorophenyl)-5-(2-hydroxyethyl)
9-methoxy,2-methyl,5,7dihydrobenzo[5,6]oxepino[4,3-c]pyridin-3(2H)-one
##STR00023##
[0217] To a stirred solution of ethyl
2-(7-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-2,3,5,7-tetrahydrobenzo[5,-
6]oxepino[4,3-c]pyridin-5-yl)acetate (example 1) (0.025 g, 0.055
mmol) in dry THF (1 mL), at 0.degree. C. Lithium Aluminium Hydride
(0.0023, 0.06 mmol, 2M in THF) was added dropwise and stirred at
same temperature for 1h. After the completion of reaction, reaction
mixture was quenched with saturated ammonium chloride solution.
Reaction mixture was extracted with DCM dried over sodium sulphate
and concentrated. The crude product was purified by Biotage
purifier, eluted in 1%-5% DCM/Methanol to yield
7-(4-chlorophenyl)-5-(2-hydroxyethyl)-9-methoxy-2-methyl-5,7-dihydrobenzo-
[5,6]oxepino[4,3-c]pyridin-3 (2H)-one as a off-white solid (8 mg,
35% yield). .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta. (ppm) 7.78
(s, 1H), 7.37 (d, J=8.4 Hz, 1H), 7.27 (d, J=7.6 Hz, 2H), 7.12 (d,
J=7.6 Hz, 2H). 7.00 (d, J=8.4 Hz, 1H), 6.68 (s, 1H), 6.34 (s, 1H),
5.92 (s, 1H), 4.70-4.60 (m, 1H), 4.50-4.45 (m, 1H), 3.72 (s, 3H),
3.60-3.48 (m, 2H), 3.43 (s, 3H), 1.82-1.70 (m, 2H). MS (ESI): mass
calcd. for C.sub.23H.sub.22ClNO.sub.4, 411.1; m/z found, 412.1
[M+H].sup.+.--
Example 8
.+-.2-(7-(4-chlorophenyl)9methoxy2methyl3oxo2,3,5,7tetrahydrobenzo[5,6]oxe-
pino[4,3-c]pyridin-5-yl)-N-ethylacetamide
##STR00024##
[0219] To a stirred solution of ethyl
2-(7-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-2,3,5,7-tetrahydrobenzo[5,-
6]oxepino[4,3-c]pyridin-5-yl)acetate (example 1) (0.5 g, 1.1 mmol)
in THF (2 mL), trimethyl aluminium (4.4 mL, 8.8 mmol) and 2 M ethyl
amine solution (4.4 mL, 8.8 mmol) was added at 0.degree. C. under
nitrogen atmosphere. The mixture was stirred for 1h at 90.degree.
C. The mixture was quenched with saturated ammonium chloride. The
residue was partitioned with ethyl acetate and water. The organic
layer was washed with cold water, dried over Na.sub.2SO.sub.4,
concentrated under reduced pressure. The crude was purified by HPLC
using Inertsil ODS (250 mm.times.4.6 mm .times.5.mu.) column with
0.01% ammonia/water and ACN as mobile phase with UV detection 254
nm was utilized. 160 mg of a mixture of diastereomer 8A and 140 mg
of a mixture of diastereomer 8B obtained.
##STR00025##
[0220] Preparative Chiral HPLC method for the separation of
diastereomers 8A and 8B:
[0221] Column: CHIRALPAK IA (250 mm .times.4.6 mm.times.5
.mu.m)
[0222] Wavelength: 254 nm UV Injection Volume: 25.0 .mu.l/min 20
deg C. Eluent: 80:20:0.1 MTBE:MeOH:DEA
Example 8C
2-((5S,7R)-7-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-2,3,5,7-tetrahydrob-
enzo[5,6]oxepino[4,3-c]pyridin-5-yl)-N-ethylacetamide
##STR00026##
[0224] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. (ppm): 7.95 (br.
s., 1H), 7.75 (s, 1H), 7.37 (d, J=8.8 Hz, 1H), 7.22 (d, J=8.4 Hz,
2H), 7.04-6.99 (m, 3H), 6.92 (s, 1H), 6.30 (s, 1H), 5.97 (s, 1H),
4.86 (t, J=7.2 Hz, 1H), 3.76 (s, 3H), 3.41 (s, 3H), 3.06-3.03 (m,
2H), 2.64-2.62 (m, 2H), 0.98 (t, J=7.2 Hz, 3H). MS (ESI): mass
calcd. for C.sub.25H.sub.25ClN.sub.2O.sub.4, 452.2; m/z found,
453.2[M+H].sup.+.
Example 8D
2-((5S,7S)-7-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-2,3,5,7-tetrahydrob-
enzo[5,6]oxepino[4,3-c]pyridin-5-yl)-N-ethylacetamide
##STR00027##
[0226] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. (ppm): 8.02 (br.
s., 1H), 7.96 (s, 1H), 7.45-7.41 (m, 3H), 7.34 (d, J=8.4 Hz, 2H),
7.07-7.04 (m, 1H), 6.44 (s, 1H), 5.94 (s, 1H), 5.46 (s, 1H), 4.52
(t, J=6.8 Hz, 1H), 3.62 (s, 3H), 3.53 (s, 3H), 3.10-3.00 (m, 2H),
2.70-2.68-2.66 (m, 2H), 1.00 (t, J=7.2 Hz, 3H). MS (ESI): mass
calcd. for C.sub.25H.sub.25ClN.sub.2O.sub.4, 452.2; m/z found,
453.2[M+H].sup.+.
Example 8E
2-((5R,7S)-7-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-2,3,5,7-tetrahydrob-
enzo[5,6]oxepino[4,3-c]pyridin-5-yl)-N-ethylacetamide
##STR00028##
[0228] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. (ppm): 7.95 (br.
s., 1H), 7.75 (s, 1H), 7.37 (d, J=8.8 Hz, 1H), 7.22 (d, J=8.4 Hz,
2H), 7.04-6.99 (m, 3H), 6.92 (s, 1H), 6.30 (s, 1H), 5.97 (s, 1H),
4.86 (t, J=7.2 Hz, 1H), 3.76 (s, 3H), 3.41 (s, 3H), 3.06-3.03 (m,
2H), 2.64-2.62 (m, 2H), 0.98 (t, J=7.2 Hz, 3H). MS (ESI): mass
calcd. for C.sub.25H.sub.25ClN.sub.2O.sub.4, 452.2; m/z found,
453.2[M+H].sup.+.
Example 8F
2-((5R,7R)-7-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-2,3,5,7-tetrahydrob-
enzo[5,6]oxepino[4,3-c]pyridin-5-yl)-N-ethylacetamide
##STR00029##
[0230] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. (ppm): 8.02 (br.
s., 1H), 7.96 (s, 1H), 7.45-7.41 (m, 3H), 7.34 (d, J=8.4 Hz, 2H),
7.07-7.04 (m, 1H), 6.44 (s, 1H), 5.94 (s, 1H), 5.46 (s, 1H), 4.52
(t, J=6.8 Hz, 1H), 3.62 (s, 3H), 3.53 (s, 3H), 3.10-3.00 (m, 2H),
2.70-2.68-2.66 (m, 2H), 1.00 (t, J=7.2 Hz, 3H). MS (ESI): mass
calcd. for C.sub.25H.sub.25ClN.sub.2O.sub.4, 452.2; m/z found,
453.2[M+H].sup.+.
[0231] Following compounds were synthesized using the above
procedure as exemplified in example 8
Example 9
.+-.2-(7-cyclohexyl-9-methoxy-2-methyl-3-oxo-2,3,5,7-tetrahydrobenzo[5,6]o-
xepino[4,3-c]pyridin-5-yl)-N-ethylacetamide
##STR00030##
[0233] This compound was synthesized and purified as described for
synthesizing compound 8 and the diastereoisomers were separated by
HPLC to give 9A and 9B using similar conditions for separating 8A
and 8B
Example 9A
.+-.2-((5S,7R)-7-cyclohexyl-9-methoxy-2-methyl-3-oxo-2,3,5,7-tetrahydroben-
zo[5,6]oxepino[4,3-c]pyridin-5-yl)-N-ethylacetamide
##STR00031##
[0235] .sup.1HNMR: (400 MHz, DMSO-d.sub.6) 7.91 (br.s, 1H) 7.83 (s,
1H) 7.36 (d, J=8.4 Hz, 1H) 7.02-7.01 (m, 1H) 6.94-6.92 (m, 1H),
6.23 (s, 1H), 4.66-4.63 (m, 1H), 4.60-4.58 (m, 1H), 3.78 (m, 3H),
3.48 (s, 3H), 3.07-3.00 (m, 2H), 2.66-2.53 (m, 2H), 1.56-1.47 (m,
4H), 1.37 (m, 1H), 1.22 (m, 1H), 1.33-0.98 (m, 6H), 0.89-0.85 (m,
2H). (ESI): mass calcd for C.sub.25H.sub.32N.sub.2O.sub.4, 424.3;
m/z found, 425.0 [M+H].sup.+.
Example 9B
.+-.2-((5S,7S)-7-cyclohexyl-9-methoxy-2-methyl-3-oxo-2,3,5,7-tetrahydroben-
zo[5,6]oxepino[4,3-c]pyridin-5-yl)-N-ethylacetamide
##STR00032##
[0237] (ESI): mass calcd for C.sub.25H.sub.32N.sub.2O.sub.4, 424.3;
m/z found, 425.0 [M+H].sup.+.
Example 10
.+-.2-(7-(cyclopropylmethyl)-9-methoxy-2-methyl-3-oxo-2,3,5,7-tetrahydrobe-
nzo[5,6]oxepino[4,3-c]pyridin-5-yl)-N-ethylacetamide
##STR00033##
[0239] Compound 10 was synthesized and purified as described for
synthesizing compound 8 and the diastereoisomers were separated by
HPLC to give 10A and 10B using similar conditions for separating 8A
and 8B
Example 10A
.+-.2-((5S,7R)-7-(cyclopropylmethyl)-9-methoxy-2-methyl-3-oxo-2,3,5,7-tetr-
ahydrobenzo[5,6]oxepino[4,3-c]pyridin-5-yl)-N-ethylacetamide
##STR00034##
[0241] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. (ppm) 7.90-7.85
(m, 2H), 7.34 (d, J=8.4 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H), 6.85 (s,
1H), 6.26 (s, 1H), 4.81 (t, J=6.0 Hz, 1H), 4.71 (t, J=6.8 Hz, 1H),
3.77 (s, 3H), 3.47 (s, 3H), 3.10-2.95 (m, 2H), 1.56-1.45 (m, 1H),
1.30-1.20 (m, 2H), 0.95 (t, J=6.8 Hz, 3H), 0.55-0.45 (m, 1H),
0.3-0.15 (m, 2H), (-)0.12-(-)0.13 (m, 2H). MS (ESI): mass
calculated for C.sub.23H.sub.28N.sub.2O.sub.4, 396.2; m/z found,
397.2[M+H].sup.+.
Example 10B
.+-.2-((5S,7S)-7-(cyclopropylmethyl)-9-methoxy-2-methyl-3-oxo-2,3,5,7-tetr-
ahydrobenzo[5,6]oxepino[4,3-c]pyridin-5-yl)-N-ethylacetamide
##STR00035##
[0243] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): .delta. (ppm) 7.93 (br.
s., 1H), 7.84 (s, 1H), 7.36 (d, J=8.4 Hz, 1H), 7.02 (d, J=8.4 Hz,
1H), 6.95 (s, 1H), 6.42 (s, 1H), 4.26 (t, J=Hz, 1H), 4.20 (t, J=Hz,
1H), 3.80 (s, 3H), 3.48 (s, 3H), 3.01-2.95 (m, 2H), 2.70-2.60 (m,
2H), 1.82-1.70 (m, 2H), 0.95 (t, J=7.2 Hz, 3H), 0.75-0.60 (m, 1H),
0.33-0.31 (m, 2H), 0.05-0.015 (m, 2H). MS (ESI): mass calculated
for C.sub.23H.sub.28N.sub.2O.sub.4, 396.2; m/z found,
397.2[M+H].sup.+.
Example 11
.+-.2-(9-methoxy-2-methyl-7-(5-methylpyridin-2-yl)-3-oxo-2,3,5,7-tetrahydr-
obenzo[5,6]oxepino[4,3-c]pyridin-5-yl)-N-ethylacetamide
##STR00036##
[0245] Compound 11 was synthesized and purified as described for
synthesizing compound 8 and the diastereoisomers were separated by
HPLC to give 11A and 11B using similar conditions for separating 8A
and 8B.
Example 11A
.+-.2-((5S,7S)-9-methoxy-2-methyl-7-(5-methylpyridin-2-yl)-3-oxo-2,3,5,7-t-
etrahydrobenzo[5,6]oxepino[4,3-c]pyridin-5-yl)-N-ethylacetamide
##STR00037##
[0247] .sup.1HNMR: (400 MHz, DMSO-d.sub.6): .delta. (ppm) 8.36 (s,
1H), 8.04 (t, J=8 Hz, 1H), 7.96 (s, 1H), 7.79 (d, J=8 Hz, 1H), 7.53
(d, J=8 Hz, 1H), 7.43 (d, J=8 Hz, 1H), 7.05-7.03 (m, 1H), 6.45 (s,
1H), 5.83 (s, 1H), 5.40 (s, 1H), 4.54-4.51 (m, 1H), 3.61 (s, 3H),
3.52 (s, 3H), 3.09-3.00 (m, 2H), 2.70-2.69 (m, 2H), 2.30 (s, 3H),
0.99 (t, J=8 Hz, 3H). (ESI): mass calcd for
C.sub.25H.sub.27N.sub.3O.sub.4, 433.1; m/z found, 434.2.0
[M+H].sup.+.
Example 11B
.+-.2-((5S,7R)-9-methoxy-2-methyl-7-(5-methylpyridin-2-yl)-3-oxo-2,3,5,7-t-
etrahydrobenzo[5,6]oxepino[4,3-c]pyridin-5-yl)-N-ethylacetamide
##STR00038##
[0249] (ESI): mass calcd for C.sub.25H.sub.27N.sub.3O.sub.4, 433.1;
m/z found, 434.2.0 [M+H].sup.+.
Example 12
.+-.2-(9-fluoro-2-methyl-3-oxo-7-phenyl-2,3,5,7-tetrahydrobenzo[5,6]oxepin-
o[4,3-c]pyridin-5-yl)-N-ethylacetamide
[0250] Compound 12 was synthesized and purified as described for
synthesizing compound 8 and the diastereoisomers were separated by
HPLC to give 12A and 12B using similar conditions for separating 8A
and 8B
Example 12A
.+-.-2-((5S,7R)-7-(4-chlorophenyl)-9-fluoro-2-methyl-3-oxo-2,3,5,7-tetrahy-
drobenzo[5,6]oxepino[4,3-c]pyridin-5-yl)-N-ethylacetamide
##STR00039##
[0252] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta. (ppm) 8.03
(br.s., 2H), 7.57-7.53 (m, 1H), 7.45 (d, J=8.0 Hz, 2H), 7.36-7.34
(m, 2H), 6.45 (s, 1H), 6.16 (d, J=8.0 Hz, 1H), 5.48 (s, 1H),
4.49-4.46 (m, 1H), 3.52 (s, 3H), 3.05-3.01 (m, 3H), 2.69-2.64 (m,
2H), 0.98 (t, J=8.0 Hz, 3H); MS(ESI): mass calcd for
C.sub.24H.sub.22ClFN.sub.2O.sub.3, 440.1; m/z found, 441.2
[M+H].sup.+.
Example 12B
.+-.2-((5S,7S)-9-fluoro-2-methyl-3-oxo-7-phenyl-2,3,5,7-tetrahydrobenzo[5,-
6]oxepino[4,3-c]pyridin-5-yl)-N-ethylacetamide
##STR00040##
[0254] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta. (ppm) 7.93 (s,
1H), 7.83 (s, 1H), 7.50-7.47 (m, 1H), 7.22 (d, J=8.0 Hz, 2H),
7.16-7.14 (m, 1H), 7.05 (d, J=8.0 Hz, 2H), 6.31 (s, 1H), 5.99 (s,
1H), 4.87-4.85 (m, 1H), 3.41 (s, 3H), 3.05-3.02 (m, 2H), 2.64-2.58
(m, 3H), 0.90 (t, J=8.0 Hz, 3H); MS(ESI): mass calcd for
C.sub.24H.sub.22ClFN.sub.2O.sub.3, 440.1; m/z found, 441.2
[M+H].sup.+.
Example 13
2-(7-(4-chlorophenyl)-2-methyl-3-oxo-9-(trifluoromethyl)-2,3,5,7-tetrahydr-
obenzo[5,6]oxepino[4,3-c]pyridin-5-yl)-N-ethylacetamide
##STR00041##
[0256] Compound 13 was synthesized and purified as described for
synthesizing compound 8 and the diastereoisomers were separated by
HPLC to give 13A and 13B using similar conditions for separating 8A
and 8B
Example 13A
.+-.2-((5S,7R)-7-(4-chlorophenyl)-2-methyl-3-oxo-9-(trifluoromethyl)-2,3,5-
,7-tetrahydrobenzo[5,6]oxepino[4,3-c]pyridin-5-yl)-N-ethylacetamide
##STR00042##
[0258] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta. (ppm) 8.15 (s,
1H), 8.01 (t, J=8 Hz, 1H), 7.85 (br.s., 1H), 7.75 (d, J=8.0 Hz,
1H), 7.47 (d, J=8.0 Hz, 2H), 7.37 (d, J=8.0 Hz, 2H), 6.67 (s, 1H),
6.48 (s, 1H), 5.57 (s, 1H), 4.49 (t, J=8.0 Hz, 1H), 3.54 (s, 3H),
3.07-3.03 (m, 2H), 2.69 (d, J=4.0 Hz, 2H), 0.98 (t, J=8.0 Hz, 3H).
MS(ESI): mass calcd for C.sub.25H.sub.22ClF.sub.3N.sub.2O.sub.3,
490.1; m/z found, 491.1 [M+H].sup.+.
Example 13B
.+-.2-((5S,7S)-7-(4-chlorophenyl)-2-methyl-3-oxo-9-(trifluoromethyl)-2,3,5-
,7-tetrahydrobenzo[5,6]oxepino[4,3-c]pyridin-5-yl)-N-ethylacetamide
##STR00043##
[0260] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta. (ppm) 7.95
(br.s., 2H), 7.79 (d, J=8 Hz, 1H), 7.67 (d, J=8 Hz, 2H), 7.24 (d,
J=8 Hz, 2H), 7.03 (d, J=8 Hz, 2H), 6.34 (s, 1H), 6.15 (s, 1H), 4.86
(t, J=7.8 Hz, 1H), 3.42 (s, 3H), 3.05-3.01 (m, 3H), 2.64-2.62 (m,
2H), 0.96 (t, J=8 Hz, 3H). MS(ESI): mass calcd for
C.sub.25H.sub.22ClF.sub.3N.sub.2O.sub.3, 490.1; m/z found, 491.1
[M+H].sup.+.
Example 14
.+-.-Ethyl-2-(7-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-b-
enzo[c]pyrido[3,4-e]azepin-5-yl)acetate
##STR00044##
[0262] To a stirred solution of (E)-ethyl
3-(5-(2-(4-chlorobenzoyl)-4-methoxyphenyl)-1-methyl-2-oxo-1,2-dihydropyri-
din-4-yl)acrylate (step F, example 1, compound VIII) (0.01 g, 0.22
mmol) in ethanol (2 mL), ammonium formate (0.280 mg, 4.4 mmol) was
added at room temperature under nitrogen atmosphere. The reaction
mixture was stirred at 95.degree. C. for 4h. After 4h heating the
reaction was monitored by LCMS. The reaction mixture was cooled to
room temperature and concentrated under reduced pressure. The
residue was partitioned with ethyl acetate and water. The organic
layer was washed with brine, dried over Na.sub.2SO.sub.4 and
concentrated under reduced pressure to get thick mass. The crude
was purified by combi-flash eluting with (0-10%) MeOH: DCM. The
pure fractions were concentrated to obtain white solid (15 mg,
15%). .sup.1HNMR (400 MHz, DMSO-d.sub.6): .delta.(ppm) 8.02 (s,
1H), 7.65 (d, J=8, 1H), 7.46-7.40 (m, 4H), 7.28-7.25 (m, 1H),
6.75-6.73 (m, 1H), 6.34 (s, 1H), 4.22-4.06 (m, 3H), 3.75 (s, 3H),
3.46 (s, 3H), 3.25-3.14 (m, 2H), 1.17 (t, J=7.2 Hz, 3H). MS(ESI):
mass calcd for C.sub.25H.sub.23ClN.sub.2O.sub.4, 450.2; m/z found,
451.2 [M+H].sup.+.
[0263] Following compounds were synthesized using the above
procedure as exemplified in example 14
Example 15
.+-.Ethyl-2-(7-cyclohexyl-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c]-
pyrido[3,4-e]azepin-5-yl)acetate
##STR00045##
[0265] MS(ESI): mass calcd for C.sub.25H.sub.30N.sub.2O.sub.4,
422.0; m/z found, 423.2 [M+H].sup.+.
Example 16
.+-.Ethyl-2-(9-methoxy-2-methyl-3-oxo-7-(pyridin-2-yl)-3,5-dihydro-2H-benz-
o[c]pyrido[3,4-e]azepin-5-yl)acetate
##STR00046##
[0267] MS (ESI): mass calculated for
C.sub.24H.sub.23N.sub.3O.sub.4, 417.2; m/z found,
418.2.1[M+H].sup.+.
Example 17
.+-.Ethyl-2-(7-(cyclopropylmethyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-
-benzo[c]pyrido[3,4-e]azepin-5-yl)acetate
##STR00047##
[0269] MS (ESI): mass calculated for
C.sub.20H.sub.19F.sub.3N.sub.2O.sub.4, 394.1; m/z found,
395.1[M+H].sup.+.
Example 18
.+-.Ethyl-2-(9-methoxy-2-methyl-3-oxo-7-(trifluoromethyl)-3,5-dihydro-2H-b-
enzo[c]pyrido[3,4-e]azepin-5-yl)acetate
##STR00048##
[0271] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. (ppm): 8.06 (s,
1H), 7.68 (d, J=8.8 Hz, 1H), 7.37-7.32 (m, 1H), 7.11 (s, 1H), 6.40
(s, 1H), 4.30-4.25 (m, 1H), 4.12-3.90 (m, 2H), 3.81 (s, 3H), 3.46
(s, 3H), 3.30-3.12 (m, 2H), 1.14 (t, J=6.8 Hz, 3H). MS (ESI): mass
calculated for C.sub.20H.sub.19F.sub.3N.sub.2O.sub.4, 408.1; m/z
found, 409.1[M+H].sup.+.
Example 19
.+-.Ethyl-2-(9-methoxy-2,7-dimethyl-3-oxo-3,5-dihydro-2H-benzo[c]pyrido[3,-
4-e]azepin-5-yl)acetate
##STR00049##
[0273] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. (ppm): 7.90 (s,
1H), 7.51 (d, J=8.8 Hz, 1H), 7.23-7.22 (m, 1H), 7.16-7.13 (m, 1H),
6.24 (s, 1H), 4.03-3.99 (m, 3H), 3.83 (s, 3H), 3.44 (s, 3H),
3.05-3.01 (m, 2H), 2.24 (s, 3H), 1.12 (t, J=7.6 Hz, 3H). MS (ESI):
mass calculated for C.sub.20H.sub.22N.sub.2O.sub.4, 354.20; m/z
found, 355.1 [M+H].sup.+.
Example 20
.+-.Ethyl-2-(9-methoxy-2-methyl-7-(5-methylpyridin-2-yl)-3-oxo-3,5-dihydro-
-2H-benzo[c]pyrido[3,4-e]azepin-5-yl)acetate
##STR00050##
[0275] .sup.1HNMR: (400 MHz, DMSO-d.sub.6) 8.29 (s, 1H), 7.98 (s,
1H), 7.98-7.76 (d, J=8 Hz, 1H), 7.69-7.67 (d, J=8 Hz, 1H),
7.58-7.56 (d, J=8 Hz, 1H), 7.21-7.18 (dd, 1H), 6.72-6.71 (m, 1H),
6.33 (s, 1H), 4.26-4.25 (m, 1H), 4.04-4.05 (m, 2H), 3.71 (s, 3H),
3.44 (s, 3H), 3.27-3.22 (dd, 1H), 3.15-3.13 (dd, 1H), 2.29 (s, 3H),
1.17-1.13 (t, J=5.2 Hz, 3H). MS (ESI): mass calculated for
C.sub.24H.sub.25N.sub.3O.sub.4, 431.2; m/z found,
432.2[M+H].sup.+.
Example 21
.+-.Ethyl-2-(7-(4-chlorophenyl)-2-isopropyl-9-methoxy-3-oxo-3,5-dihydro-2H-
-benzo[c]pyrido[3,4-e]azepin-5-yl)acetate
##STR00051##
[0277] MS (ESI): mass calculated for
C.sub.27H.sub.27ClN.sub.2O.sub.4, 478.1; m/z found,
479.1[M+H].sup.+.
Example 22
.+-.Ethyl-2-(7-(4-chlorophenyl)-9-fluoro-2-methyl-3-oxo-3,5-dihydro-2H-ben-
zo[c]pyrido[3,4-e]azepin-5-yl)acetate
##STR00052##
[0279] MS(ESI): mass calcd for C.sub.24H.sub.20ClFN.sub.2O.sub.3,
438.1; m/z found, 439.1 [M+H].sup.+.
Example 23
.+-.Ethyl-2-(7-(2,6-difluorophenyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2-
H-benzo[c]pyrido[3,4-e]azepin-5-yl)acetate
##STR00053##
[0281] MS(ESI): mass calcd for
C.sub.25H.sub.22F.sub.2N.sub.2O.sub.4, 452.1; m/z found, 453.2
[M+H].sup.+.
Example 24
.+-.Ethyl-2-(7-(4-chloro-2-methylphenyl)-9-methoxy-2-methyl-3-oxo-3,5-dihy-
dro-2H-benzo[c]pyrido[3,4-e]azepin-5-yl)acetate
##STR00054##
[0283] MS(ESI): mass calcd for C.sub.26H.sub.25ClN.sub.2O.sub.4,
464.2; m/z found, 465.2 [M+H].sup.+.
Example 25
.+-.2-(7-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-3,5dihydro-2H-benzo[c]p-
yrido[3,4-e]azepin-5-yl)-N-ethylacetamide
##STR00055##
[0285] The compound was synthesized according to the procedure for
example 8. .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta. (ppm) 8.13
(br. s., 1H), 7.99 (s, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.48-7.38 (m,
4H), 7.25-7.24 (m, 1H), 6.73 (d, J=2.0 Hz, 1H). 6.35 (s, 1H), 4.24
(t, J=7.2 Hz, 1H), 3.73 (s, 3H), 3.44 (s, 3H), 3.08-3.04 (m, 2H),
2.93-2.91 (m, 2H), 1.00 (t, J=7.6 Hz, 3H). MS (ESI): mass calcd.
for C.sub.25H.sub.24ClN.sub.3O.sub.3, 449.1; m/z found,
450.4[M+H].sup.+.
[0286] Chiral Separation Conditions, 25A and 25B
Analytical Conditions:
[0287] Column: chiralpak IA (250 mm .times.4.6 mm .times.5 m)
Mobile phase: MtBe:IPA with 0.1% TFA (70:30) Flow rate: 1.0 mL/min;
Injection Volume: 20.00 ul PDA detector, wavelength: 261.0 nm
Example 25A
(S)-2-(7-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c]-
pyrido[3,4-e]azepin-5-yl)-N-ethylacetamide
##STR00056##
[0289] MS (ESI): mass calcd. for C.sub.25H.sub.24ClN.sub.3O.sub.3,
449.1; m/z found, 450.2[M+H].sup.+.
Example 25B
(R)-2-(7-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c]-
pyrido[3,4-e]azepin-5-yl)-N-ethylacetamide
##STR00057##
[0291] MS (ESI): mass calcd. for C.sub.25H.sub.24ClN.sub.3O.sub.3,
449.1; m/z found, 450.2[M+H].sup.+.
[0292] The following compounds were synthesized using the procedure
for synthesizing 25
Example 26
.+-.2-(7-cyclohexyl-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c]pyrido-
[3,4-e]azepin-5-yl)-N-ethylacetamide
##STR00058##
[0294] .sup.1H NMR (DMSO-d6), .delta. (ppm): 8.02 (br.s., 1H) 7.90
(s, 1H) 7.48-7.46 (d J=8.4 Hz, 1H) 7.16-7.15 (m, 1H) 7.12-7.10 (m,
1H), 6.28 (s, 1H), 4.01 (t, J=6.8 Hz, 1H), 3.83 (s, 3H), 3.43 (s,
3H), 3.04-2.97 (m, 2H), 2.89-2.70 (m, 3H), 1.82-1.00 (m, 9H), 0.96
(t, J=7.2 Hz, 3H), 0.67-0.59 (m, 1H). MS(ESI): mass calcd for
C.sub.25H.sub.31N.sub.3O.sub.3, 421.2; m/z found,
422.5[M+H].sup.+.
[0295] Compound 26 was chiral separated (26A and 26B) following the
procedures used for separating 25A and 25B
Example 26A
(S)-2-(7-cyclohexyl-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c]pyrido-
[3,4-e]azepin-5-yl)-N-ethylacetamide
##STR00059##
[0297] MS(ESI): mass calcd for C.sub.25H.sub.31N.sub.3O.sub.3,
421.2; m/z found, 422.5[M+H].sup.+.
Example 26B
(R)-2-(7-cyclohexyl-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c]pyrido-
[3,4-e]azepin-5-yl)-N-ethylacetamide
##STR00060##
[0299] MS(ESI): mass calcd for C.sub.25H.sub.31N.sub.3O.sub.3,
421.2; m/z found, 422.5[M+H].sup.+.
Example 27
.+-.2-(9-methoxy-2-methyl-3-oxo-7-(pyridin-2-yl)-3,5-dihydro-2H-benzo[c]py-
rido[3,4-e]azepin-5-yl)-N-ethylacetamide
##STR00061##
[0301] .sup.1H NMR (DMSO-d6): .delta. (ppm) 8.45 (d, J=4 Hz, 1H),
8.14 (br. s., 1H), 7.97 (s, 1H), 7.92-7.82 (m, 2H), 7.57 (d, J=12
Hz, 1H), 7.42-7.39 (m, 1H), 7.20-7.18 (m, 1H), 6.71 (s, 1H), 6.36
(s, 1H), 4.31 (t, J=6.4 Hz, 1H), 3.71 (s, 3H), 3.44 (s, 3H),
3.08-3.05 (m, 2H), 2.94-2.93 (m, 2H), 1.01 (t, J=7.2 Hz, 3H). MS
(ESI): mass calculated for C.sub.24H.sub.24N.sub.4O.sub.3, 416.1;
m/z found, 417.3.1[M+H].sup.+.
[0302] Compound 27 was chiral separated (27A and 27B) following the
procedures used for separating 25A and 25B
Example 27A
(S)-2-(9-methoxy-2-methyl-3-oxo-7-(pyridin-2-yl)-3,5-dihydro-2H-benzo[c]py-
rido[3,4-e]azepin-5-yl)-N-ethylacetamide
##STR00062##
[0304] MS (ESI): mass calculated for
C.sub.24H.sub.24N.sub.4O.sub.3, 416.1; m/z found,
417.3.1[M+H].sup.+.
Example 27B
(R)-2-(9-methoxy-2-methyl-3-oxo-7-(pyridin-2-yl)-3,5-dihydro-2H-benzo[c]py-
rido[3,4-e]azepin-5-yl)-N-ethylacetamide
##STR00063##
[0306] MS (ESI): mass calculated for
C.sub.24H.sub.24N.sub.4O.sub.3, 416.1; m/z found,
417.3.1[M+H].sup.+.
Example 28
.+-.2-(7-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c]-
pyrido[3,4-e]azepin-5-yl)acetamide
##STR00064##
[0308] .sup.1H NMR (DMSO-d6): .delta. (ppm) 12.28 (s, 1H), 8.01 (s,
1H), 7.63 (d, J=8.4 Hz, 1H), 7.45-7.40 (m, 4H), 7.26-7.23 (m, 1H),
6.74-6.71 (m, 1H), 6.31 (s, 1H), 4.17 (t, J=3.8 Hz, 1H), 3.73 (s,
3H), 3.45 (s, 3H), 3.13-3.08 (m, 3H). MS (ESI): mass calcd. for
C.sub.23H.sub.20ClN.sub.3O.sub.3, 421.8; m/z found, 423.1
[M+H].sup.+.
Example 29
.+-.2-(7-(4-chlorophenyl)-9-hydroxy-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c]-
pyrido[3,4-e]azepin-5-yl)-N-ethylacetamide
##STR00065##
[0310] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. (ppm): 9.79 (s,
1H), 8.12 (br.s., 1H), 7.94 (s, 1H), 7.5 (d, J=8.8 Hz, 1H),
7.45-7.38 (m, 4H), 7.04-7.01 (m, 1H), 6.60-6.59 (m, 1H), 6.33 (s,
1H), 4.22 (t, J=7.2 Hz, 1H), 3.43 (s, 3H), 3.08-3.03 (m, 2H),
2.93-2.88 (m, 2H), 1.00 (t, J=7.2 Hz, 3H). MS (ESI): mass
calculated for C.sub.24H.sub.22ClN.sub.3O.sub.3, 435.90; m/z found,
436.1[M+H].
Example 30
.+-.2-(7-(cyclopropylmethyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-benzo-
[c]pyrido[3,4-e]azepin-5-yl)-N-ethylacetamide
##STR00066##
[0312] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta. (ppm) 8.03 (br.
s, 1H), 7.91 (s, 1H), 7.49 (d, J=8.8 Hz, 1H), 7.20 (d, J=2.8 Hz,
1H), 7.13 (dd, J1=2.4 Hz, J2=8.8 Hz, 1H), 6.28 (s, 1H), 4.05 (t,
J=7.2 Hz, 1H), 3.83 (s, 3H), 3.44 (s, 3H), 3.10-2.95 (m, 2H),
2.85-2.76 (m, 3H), 2.34-2.25 (m, 1H), 0.96 (t, J=7.2 Hz, 3H),
0.65-0.55 (m, 1H), 0.24-0.15 (m, 2H), (-) 0.05-(-) 0.12 (m, 2H). MS
(ESI): mass calcd. for C.sub.23H.sub.27N.sub.3O.sub.3, 393.2; m/z
found, 394.2 [M+H].sup.+.
[0313] Compound 30 was chiral separated (30A and 30B) following the
procedures used for separating 25A and 25B
Example 30A
(S)-2-(7-(cyclopropylmethyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-benzo-
[c]pyrido[3,4-e]azepin-5-yl)-N-ethylacetamide
##STR00067##
[0315] MS (ESI): mass calcd. for C.sub.23H.sub.27N.sub.3O.sub.3,
393.2; m/z found, 394.2 [M+H].sup.+.
Example 30B
(R)-2-(7-(cyclopropylmethyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-benzo-
[c]pyrido[3,4-e]azepin-5-yl)-N-ethylacetamide
##STR00068##
[0317] MS (ESI): mass calcd. for C.sub.23H.sub.27N.sub.3O.sub.3,
393.2; m/z found, 394.2 [M+H].sup.+.
Example 31
.+-.2-(7-(4-chlorophenyl)-9-(difluoromethoxy)-2-methyl-3-oxo-3,5-dihydro-2-
H-benzo[c]pyrido[3,4-e]azepin-5-yl)-N-ethylacetamide
##STR00069##
[0319] MS (ESI): mass calculated for
C.sub.25H.sub.22ClF.sub.2N.sub.3O.sub.3, 485.1; m/z found,
486.1[M+H].sup.+.
Example 32
.+-.2-(9-methoxy-2-methyl-3-oxo-7-(trifluoromethyl)-3,5-dihydro-2H-benzo[c-
]pyrido[3,4-e]azepin-5-yl)-N-ethylacetamide
##STR00070##
[0321] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. (ppm): 8.10 (t,
J=5.2 Hz, 1H), 8.04 (s, 1H), 7.68 (d, J=8.8 Hz, 1H), 7.38-7.32 (m,
1H), 7.11 (s, 1H), 6.39 (s, 1H), 4.35-4.30 (m, 1H), 3.85 (s, 3H),
3.44 (s, 3H), 3.08-2.90 (m, 4H), 0.97 (t, J=6.8 Hz, 3H). MS (ESI):
mass calculated for C.sub.20H.sub.20F.sub.3N.sub.3O.sub.3, 407.1;
m/z found, 408.3[M+H].sup.+.
[0322] Compound 32 was chiral separated (32A and 32B) following the
procedures used for separating 25A and 25B
Example 32A
(S)-2-(9-methoxy-2-methyl-3-oxo-7-(trifluoromethyl)-3,5-dihydro-2H-benzo[c-
]pyrido[3,4-e]azepin-5-yl)-N-ethylacetamide
##STR00071##
[0324] MS (ESI): mass calculated for
C.sub.20H.sub.20F.sub.3N.sub.3O.sub.3, 407.1; m/z found,
408.3[M+H].sup.+.
Example 32B
[0325]
(R)-2-(9-methoxy-2-methyl-3-oxo-7-(trifluoromethyl)-3,5-dihydro-2H--
benzo[c]pyrido[3,4-e]azepin-5-yl)-N-ethylacetamide
##STR00072##
[0326] MS (ESI): mass calculated for
C.sub.20H.sub.20F.sub.3N.sub.3O.sub.3, 407.1; m/z found,
408.3[M+H].sup.+.
Example 33
.+-.2-(7-(4-cyanophenyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c]p-
yrido[3,4-e]azepin-5-yl)-N-ethylacetamide
##STR00073##
[0328] .sup.1H NMR (DMSO-d6), .delta. (ppm): 8.15 (t, J=7.4 Hz,
1H), 8.00 (s, 1H), 7.84 (d, J=8.4 Hz, 1H), 7.64 (d, J=8.8 Hz, 1H),
7.56 (d, J=8.4 Hz, 2H), 7.41-7.45 (m, 1H), 7.25-7.28 (m, 1H), 6.71
(d, J=2.8 Hz, 1H), 6.36 (s, 1H), 4.28 (t, J=7.2 Hz, 1H), 3.73 (s,
3H), 3.44 (s, 3H), 3.03-3.08 (m, 2H), 2.92-2.95 (m, 2H), 1.01 (t,
J=8.0 Hz, 3H); MS(ESI): mass calcd for
C.sub.26H.sub.24N.sub.4O.sub.3, 440.1; m/z found,
441.2[M+H].sup.+.
Example 34
.+-.2-(9-methoxy-2-methyl-7-(5-methylpyridin-2-yl)-3-oxo-3,5-dihydro-2H-be-
nzo[c]pyrido[3,4-e]azepin-5-yl)-N-ethylacetamide
##STR00074##
[0330] .sup.1HNMR: (400 MHz, DMSO-d.sub.6), .delta. (ppm): 8.29 (s,
1H), 8.13 (br.s., 1H), 7.96 (s, 1H), 7.81 (d, J=8 Hz, 1H), 7.68 (d,
J=5.2 Hz, 1H), 7.55 (d, J=8 Hz, 1H), 7.19-7.17 (m, 1H), 6.39 (s,
1H), 4.28 (t, J=6.4 Hz, 1H), 3.71 (s, 3H), 3.44 (s, 3H), 3.08-3.04
(m, 2H), 2.93-2.91 (m, 2H), 2.29 (s, 3H), 1.03 (t, J=8 Hz, 3H).
MS(ESI): mass calcd for C.sub.25H.sub.26N.sub.4O.sub.3, 430.1; m/z
found, 431.2[M+H].sup.+.
Example 35
.+-.2-(7-(4-chlorophenyl)-2-methyl-3-oxo-9-(trifluoromethyl)-3,5-dihydro-2-
H-benzo[c]pyrido[3,4-e]azepin-5-yl)-N-ethylacetamide
##STR00075##
[0332] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta. (ppm) 8.20 (s,
1H), 8.13 (br.s., 1H), 8.01 (d, J=8.0 Hz, 1H), 7.94 (d, J=8.0 Hz,
1H), 7.53 (s, 1H), 7.46 (d, J=8.0 Hz, 2H), 7.37 (d, J=8.0 Hz, 2H),
6.39 (s, 1H), 4.23 (t, J=8.0 Hz, 1H), 3.47 (s, 3H), 3.09-3.03 (m,
2H), 2.95 (d, J=8.0 Hz, 2H), 1.00 (t, J=8.0 Hz, 3H). MS(ESI): mass
calcd for C.sub.25H.sub.21ClF.sub.3N.sub.3O.sub.2, 487.1; m/z
found, 488.3[M+H].sup.+ LCMS: 488.3 [M+H].
Example 36
.+-.2-(7-(4-chlorophenyl)-2-isopropyl-9-methoxy-3-oxo-3,5-dihydro-2H-benzo-
[c]pyrido[3,4-e]azepin-5-yl)-N-ethylacetamide
##STR00076##
[0334] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): 8.13 (br. s., 1H), 7.89
(s, 1H), 7.66 (d, J=8.4 Hz, 1H), 7.50-7.40 (m, 4H), 7.27-7.23 (m,
1H), 6.75 (d, J=2.4 Hz, 1H), 6.35 (s, 1H), 5.10-4.95 (m, 1H), 4.25
(t, J=7.2 Hz, 1H), 3.74 (s, 3H), 3.10-3.05 (m, 2H), 2.92 (d, J=6.8
Hz, 2H), 1.38 (d, J=6.4 Hz, 3H), 1.26 (d, J=7.2 Hz, 3H), 1.01 (t,
J=7.6 Hz, 3H); MS(ESI): mass calcd for
C.sub.27H.sub.28ClN.sub.3O.sub.3, 477.1; m/z found,
478.1[M+H].sup.+.
Example 37
.+-.2-(7-(4-chlorophenyl)-9-fluoro-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c]p-
yrido[3,4-e]azepin-5-yl)-N-ethylacetamide
##STR00077##
[0336] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta. (ppm) 8.13 (t,
J=8 Hz, 1H), 8.06 (s, 1H), 7.77-7.73 (m, 1H), 7.56-7.51 (m, 1H),
7.46-7.36 (m, 4H), 7.11-7.086 (dd, J=4 Hz, J=4 Hz, 1H), 6.36 (s,
1H), 4.22 (t, J=8.0 Hz, 1H), 3.45 (s, 3H), 3.09-3.03 (m, 2H),
2.94-2.92 (m, 2H), 1.00 (t, J=8.0 Hz 3H). MS(ESI): mass calcd for
C.sub.24H.sub.21ClFN.sub.3O.sub.2, 437.1; m/z found,
438.1[M+H].sup.+.
Example 38
.+-.2-(7-(2,6-difluorophenyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-benz-
o[c]pyrido[3,4-e]azepin-5-yl)-N-ethylacetamide
##STR00078##
[0338] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta. (ppm) 8.06-8.05
(m, 2H), 7.64 (d, J=8.4 Hz, 1H), 7.56-7.45 (m, 1H), 7.23-7.20 (m,
1H), 7.10-7.08 (m, 2H), 6.59 (s, 1H), 6.36 (s, 1H), 4.33 (t, J=6.8
Hz, 1H), 3.73 (s, 3H), 3.48 (s, 3H), 3.05-3.03 (m, 2H), 2.89 (d,
J=Hz, 2H), 1.00 (t, J=7.2 Hz, 3H). MS (ESI): mass calculated for
C.sub.25H.sub.23F.sub.2N.sub.3O.sub.3, 451.2; m/z found,
452.2[M+H].sup.+.
Example 39
.+-.2-(7-(4-chloro,2-methylphenyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-
-benzo[c]pyrido[3,4-e]azepin-5-yl)-N-ethylacetamide
##STR00079##
[0340] .sup.1H NMR (DMSO-d.sub.6, 400 MHz), .delta. (ppm): 8.09
(br. s., 1H), 8.03 (s, 1H), 7.62 (d, J=8.8 Hz, 1H), 7.27 (s, 1H),
7.25-7.20 (m, 2H), 6.98 (d, J=6.4 Hz, 1H), 6.44 (d, J=2.4 Hz, 1H),
6.31 (s, 1H), 4.28 (t, J=8.4 Hz, 1H), 3.67 (s, 3H), 3.48 (s, 3H),
3.10-2.78 (m, 4H), 1.94 (s, 3H), 1.00 (t, J=7.2 Hz, 3H); MS(ESI):
mass calcd for C.sub.26H.sub.26ClN.sub.3O.sub.3, 463.1; m/z found,
464.1[M+H].sup.+.
Example 40
.+-.2-(7-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c]-
pyrido[3,4-e]azepin-5-yl)-N-(4-hydroxyphenyl)acetamide
##STR00080##
[0342] .sup.1H NMR (DMSO-d.sub.6): -.delta. (ppm) 9.96 (s, 1H),
9.11 (br.s., 1H), 8.02 (s, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.45-7.40
(m, 4H), 7.33 (d, J=7.6 Hz, 2H), 7.26-7.24 (m, 1H), 6.73 (d, J=2.8
Hz, 1H), 6.66 (d, J=8.4 Hz, 2H), 6.41 (s, 1H), 4.31 (t, J=6.8 Hz,
1H), 3.73 (s, 3H), 3.45 (s, 3H), 3.12-3.08 (m, 2H); MS (ESI): mass
calcd for C.sub.29H.sub.24ClN.sub.3O.sub.4, 513.1; m/z found, 514.4
[M+H].sup.-.
[0343] Compound 40 was chiral separated (40A and 40B) following the
procedures used for separating 25A and 25B
Example 40A
(S)-2-(7-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c]-
pyrido[3,4-e]azepin-5-yl)-N-(4-hydroxyphenyl)acetamide
##STR00081##
[0345] MS (ESI): mass calcd for C.sub.29H.sub.24ClN.sub.3O.sub.4,
513.1; m/z found, 514.4 [M+H].sup.+.
Example 40B
(R)-2-(7-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c]-
pyrido[3,4-e]azepin-5-yl)-N-(4-hydroxyphenyl)acetamide
##STR00082##
[0347] MS (ESI): mass calcd for C.sub.29H.sub.24ClN.sub.3O.sub.4,
513.1; m/z found, 514.4 [M+H].sup.+.
Example 41
.+-.7-(4-chlorophenyl)-9-methoxy-2,5-dimethyl-2H-benzo[c]pyrido[3,4-e]azep-
in-3(5H)-one
##STR00083##
[0348] Step a:
N-(1-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)ethyl)-2-methylpropa-
ne-2-sulfinamide
[0349] To a stirred solution of
(E)-N-((5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)methylene)-2-methy-
lpropane-2-sulfinamide (X, 0.3 g, 0.94 mmol) in dry THF was cooled
to -78.degree. C. and then methylmagnesium bromide (0.13 mL, 1.12
mmol) was added dropwise and stirred at same temperature for 2h and
then stirred at room temperature for another 1h. Reaction mixture
was quenched with ammonium chloride solution and extracted with
ethylacetate (25 mL.times.2). The organic layer was dried,
concentrated under vacuum and purified by column chromatography
using methanol/DCM as eluent to get
N-(1-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)ethyl)-2-methylpropa-
ne-2-sulfinamide (0.27 g, 86%) as yellow solid. MS (ESI): mass
calcd for C.sub.12H.sub.19BrN.sub.2O.sub.2S, 334.0; m/z found,
335.0 [M+H].sup.+.
Step b:
N-(1-(5-(2-(4-chlorobenzoyl)-4-methoxyphenyl)-1-methyl-2-oxo-1,2-d-
ihydropyridin-4-yl)ethyl)-2-methylpropane-2-sulfinamide
[0350] To a stirred solution of
N-(1-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)ethyl)-2-methylpropa-
ne-2-sulfinamide (XI, 0.33 g, 0.98 mmol) and
(4-chlorophenyl)(5-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl-
)phenyl)methanone (VII, 0.441 g, 1.18 mmol) in toluene (20 mL) To
this mixture, was added sodium bicarbonate (249 mg, 2.96 mmol) and
Pd(PPh.sub.3).sub.4 (0.114 g, 0.098 mmol) nitrogen was purged for
10 min at room temperature in inert condition. The reaction mixture
was heated to 110.degree. C. and stirred for 16h. To the reaction
mixture water was added and extracted with ethyl acetate, the
organic layer was dried over by sodium sulfate and concentrated.
The crude product was purified by column chromatography the product
eluted at 6% of MeOH/DCM. to get the product (280 mg, 57% yield),
MS (ESI): mass calcd. for C.sub.26H.sub.29ClN.sub.2O.sub.4S, 500.2;
m/z found, 501.1 [M+H].sup.+.
Step C:
7-(4-chlorophenyl)-9-methoxy-2,5-dimethyl-2H-benzo[c]pyrido[3,4-e]-
azepin-3(5H)-one
[0351] To a stirred solution of
N-(1-(5-(2-(4-chlorobenzoyl)-4-methoxyphenyl)-1-methyl-2-oxo-1,2-dihydrop-
yridin-4-yl)ethyl)-2-methylpropane-2-sulfinamide (XII, 0.280 g,
0.56 mmol) in 4N HCl in dioxane (5 mL) was stirred at room
temperature for 1h. After completion of reaction the solvent was
evaporated then crude residue was basified with sodium bicarbonate
and organic layer was extracted with DCM then dried over by sodium
sulfate and concentrated and the crude was purified by column
chromatography by using 5% methanol/DCM as eluent to get the
compound 41 as pale yellow solid. (140 mg, 66% yield).
[0352] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta. (ppm) 7.98 (s,
1H), 7.60 (d, J=9.2 Hz, 1H), 7.46-7.41 (m, 4H), 7.25-7.20 (m, 1H),
6.74 (d, J=2.4 Hz, 1H), 6.35 (s, 1H), 3.94 (q, J=6.1 Hz, 1H), 3.73
(s, 3H), 3.45 (s, 3H), 1.62 (d, J=6.4 Hz, 3H). MS (ESI): mass
calculated for C.sub.22H.sub.19ClN.sub.2O.sub.2, 378.1; m/z found,
379.1[M+H].sup.+.
[0353] Compound 41 was chiral separated (41A and 41B) following the
procedures used for separating 25a and 25b
Example 41A
(S)-7-(4-chlorophenyl)-9-methoxy-2,5-dimethyl-2H-benzo[c]pyrido[3,4-e]azep-
in-3(5H)-one
##STR00084##
[0355] MS (ESI): mass calculated for
C.sub.22H.sub.19ClN.sub.2O.sub.2, 378.1; m/z found,
379.1[M+H].sup.+.
Example 41B
(R)-7-(4-chlorophenyl)-9-methoxy-2,5-dimethyl-2H-benzo[c]pyrido[3,4-e]azep-
in-3(5H)-one
##STR00085##
[0357] MS (ESI): mass calculated for
C.sub.22H.sub.19ClN.sub.2O.sub.2, 378.1; m/z found,
379.1[M+H].sup.+.
Example 42
.+-.7-(4-chlorophenyl)-9-methoxy-2-methyl-2H-benzo[c]pyrido[3,4-e]azepin-3-
(5H)-one
##STR00086##
[0359] The compound was synthesized using the procedure in the
example 41
[0360] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta. (ppm) 8.03 (s,
1H), 7.60 (d, J=8.8 Hz, 1H), 7.47-7.41 (m, 4H), 7.23 (dd, J=2.4 Hz,
8.8 Hz, 1H), 6.71 (d, J=2.8 Hz, 1H), 6.46 (s, 1H), 4.70 (d, J=10.0
Hz, 1H), 3.86 (d, J=10 Hz, 1H), 3.72 (s, 3H), 3.45 (s, 3H). MS
(ESI): mass calcd. for C.sub.21H.sub.17ClN.sub.2O.sub.2, 364.1; m/z
found, 365.1 [M+H].sup.+.
Example 43
.+-.2-(7-(4-chlorophenyl)-2-methyl-3-oxo-9-(trifluoromethyl)-3,5-dihydro-2-
H benzo[c]pyrido[3,4-e]azepin-5-yl)acetic acid
##STR00087##
[0361] Step A:
2-(7-(4-chlorophenyl)-2-methyl-3-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-b-
enzo[c]pyrido[3,4-e]azepin-5-yl)acetic acid
[0362] Ammonium formate (0.41 g, 0.650 mmol) was added to a stirred
solution of
3-(5-(2-(4-chlorobenzoyl)-4-(trifluoromethyl)phenyl)-1-methyl-2-oxo-1,2-d-
ihydropyridin-4-yl)acrylic acid (0.150 g, 0.325 mmol) dissolved in
ethanol (5 mL), was carried out in seal tube at 90.degree. C. After
15h the reaction mixture was cooled to room temperature and
concentrated to get mass, which was taken in ethyl acetate and
water. The organic layer was separated and dried over sodium
sulfate and concentrated to get residue. The crude was purified by
comb flash eluting with 0-80% ethyl acetate/hexane. The pure
fractions were concentrated to obtain
2-(7-(4-chlorophenyl)-2-methyl-3-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-b-
enzo[c]pyrido[3,4-e]azepin-5-yl)acetic acid (0.08 g, 57% yield) as
a off-white solid. .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta.
(ppm) 12.32 (s, 1H), 8.01 (s, 1H), 8.02-8.00 (m, 1H), 7.96-7.94 (d,
J=8 Hz, 1H), 7.54 (s, 1H), 7.50-7.48 (d, J=8 Hz, 2H), 7.39-7.37 (d,
J=8 Hz, 2H), 6.36 (s, 1H), 4.176 (t, J=8 Hz, 1H), 3.47 (s, 3H),
3.17-3.12 (m, 2H); MS(ESI): mass calcd for
C.sub.23H.sub.16ClF.sub.3N.sub.2O.sub.3, 460.1; m/z found,
461.1[M+H].sup.+.
Example 44
.+-.2-(7-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c]-
pyrido[3,4-e]azepin-5-yl)acetic acid
##STR00088##
[0364] To a stirred solution of ethyl
2-(7-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c]pyr-
ido[3,4-e]azepin-5-yl)acetate (2.1 g, 4.65 mmol) in THF (30 ml) was
added 1N NaOH (9.3 ml, 9.31 mmol) and stirred at rt for 3 hours.
Reaction mixture was neutralized with 1N HCl solution (9.3 ml) and
extracted with 5% MeOH/DCM (50 ml.times.2). The organic layer was
dried over sodium sulphate and concentrated under vacuum to get
compound 44 (1.95 g, 98.9%) as off-white solid. MS(ESI): mass calcd
for C.sub.23H.sub.19ClN.sub.2O.sub.4, 422.1; m/z found,
423.1[M+H].sup.+.
Example 45
.+-.tert-butyl
((7-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c]pyri-
do[3,4-e]azepin-5-yl)methyl)carbamate
##STR00089##
[0366] To a stirred solution of
2-(7-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c]pyr-
ido[3,4-e]azepin-5-yl)acetic acid (example 44, 0.4 g, 0.945 mmol)
in t-BuOH (20 mL), TEA (0.198 mL, 1.41 mmol), diphenylphosphoryl
azide (0.225 mL, 1.04 mmol) at room temperature. The mixture was
stirred at 105.degree. C. for 24 h. The mixture was cooled to room
temperature and concentrated under vacuum. The crude was dissolved
in ethyl acetate and washed with saturated NaHCO.sub.3 solution and
brine, dried over sodium sulphate, concentrated under reduced
pressure. The crude was purified by combiflash purifier by using
5-100% ethyl acetate/hexane as the eluent to get the product as off
white solid. (0.15 g, 32% yield). .sup.1H NMR (DMSO-d.sub.6, 400
MHz): .delta. (ppm) 7.99 (s, 1H), 7.61 (d, J=8.4 Hz, 1H), 7.50 (d,
J=8.4 Hz, 2H), 7.43 (d, J=8.8 Hz, 2H), 7.24-7.22 (m, 1H), 7.01-6.92
(m, 1H), 6.75 (d, J=2.8 Hz, 1H), 6.42 (s, 1H), 3.90-3.86 (m, 2H),
3.73 (s, 3H), 3.70-3.63 (m, 1H), 3.44 (s, 3H), 1.32 (s, 9H). MS
(ESI): mass calcd. for C.sub.27H.sub.28ClN.sub.3O.sub.4, 493.2; m/z
found, 494.1 [M+H].sup.+.
Example 46
.+-.N-((7-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c-
]pyrido[3,4-e]azepin-5-yl)methyl)acetamide
##STR00090##
[0367] Step A:
5-(aminomethyl)-7-(4-chlorophenyl)-9-methoxy-2-methyl-2H-benzo[c]pyrido[3-
,4-e]azepin-3(5H)-one hydrochloride
[0368] To a stirred solution of tert-butyl
((7-(4-chlorophenyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c]pyri-
do[3,4-e]azepin-5-yl)methyl)carbamate (example 45, 0.15 g, 0.3
mmol) in dioxan (1 mL), dioxin.HCl (5 mL) at 0.degree. C. under
nitrogen atmosphere. The mixture was concentrated under vacuum. The
crude was washed with diethyl ether twice and dried under vacuum
(0.1 g crude). MS (ESI): mass calcd. for
C.sub.22H.sub.21Cl.sub.2N.sub.3O.sub.2, 393.1; m/z found,
394.1[M+H].sup.+.
[0369] Step B: To a stirred solution of
5-(aminomethyl)-7-(4-chlorophenyl)-9-methoxy-2-methyl-2H-benzo[c]pyrido[3-
,4-e]azepin-3(5H)-one hydrochloride (XIII, 0.1 g crude, 0.25 mmol)
in DCM (5 mL), triethyl amine (0.052 mL, 0.375 mmol) at 0.degree.
C. under nitrogen atmosphere. The mixture was stirred for 15 mins.
Then acetyl chloride (0.021 mL, 0.3 mmol) was added at 0.degree. C.
The mixture was stirred for 1 h at room temperature. The mixture
was quenched with water and extracted with DCM, dried over sodium
sulphate, and dried under vacuum (0.006 g). .sup.1H NMR
(DMSO-d.sub.6, 400 MHz): .delta. (ppm) 8.06 (br.s., 1H), 7.99 (s,
1H), 7.61 (d, J=8.4 Hz, 1H), 7.50 (d, J=8.4 Hz, 2H), 7.43 (d, J=8.8
Hz, 2H), 7.24-7.22 (m, 1H), 6.73 (d, J=2.8 Hz, 1H), 6.4 (s, 1H),
3.9-3.85 (m, 2H), 3.72 (s, 3H), 3.71-3.69 (m, 1H), 3.48 (s, 3H),
1.7 (s, 3H). MS (ESI): mass calcd. for
C.sub.24H.sub.22ClN.sub.3O.sub.3, 435.13; m/z found,
436.2[M+H].sup.+.
Biological Methods
BRD4 AlphaLISA (Perkin Elmer)
[0370] Compounds were diluted by step-down dilution method (final
concentration of DMSO was 1%) and added to the wells of a 384 well
opti plate at desired concentrations. 5 nM BDR4-BD1 enzyme
(produced in-house) and 12 nM of biotinylated substrate were added
to the wells, covered and incubated at room temperature (RT) for 1
h. At the end of 1 h 250 ng of GSH acceptor beads were added to the
well and incubated for 1 h at RT; then 500 ng of streptavidin donor
beads were added and incubated again for 1 h at RT. Plates were
read in a Pherastar reader at 680 nm excitation and 570 nm
emission. As detailed above, compounds were tested for both BRD4
enzyme inhibitory activities and IC.sub.50 were determined. The
activities of selected compounds are listed in Table 1
Anticancer Activity: Alamar Blue Assay
[0371] The impact of the compounds on cancer cell proliferation was
determined using the AML cell line MV4-11 (ATCC) in a 3-day
proliferation assay. MV4-11 cells were maintained in RPMI
supplemented with 10% FBS at 37.degree. C., 5% CO.sub.2. For
compound testing, MV4-11 cells were plated in a 96-well black
bottom plate at a density of 15,000 cells/well in 100 .mu.L culture
media and incubated at 37.degree. C. overnight. Compound dilution
series were prepared in DMSO via a 3-fold serial dilution from
10004 to 0.00504. The DMSO dilution series were then diluted with
media, with the final compound concentrations added to the wells
ranging from 1004 to 0.000504. After the additions of compounds,
the cells were incubated for 72h and the numbers of viable cells
were determined using the Alamar Blue assay (Invitrogen), according
the manufacturers suggested protocol. The fluorescent readings from
the Alamar Blue assay were normalized to the DMSO treated cells and
analyzed using the GraphPad Prism software with sigmoidal curve
fitting to obtain EC.sub.50. The selected compounds activities are
listed in Table 1.
TABLE-US-00001 TABLE 1 Selected list of compounds with BRD4-BD1
IC.sub.50 and Anti-cancer activity BRD4_BD1 MV4-11 Compound
IC50_.mu.M EC50_.mu.M 1 0.024 ND 2 0.01 0.001 8F 0.012 0.024 11
0.061 0.175 14 0.003 0.002 18 0.122 ND 19 0.176 ND 23 0.001 0.005
25 0.0016 0.003 26 0.002 0.008 27 0.0044 0.112 28 0.036 0.326 30
0.01 0.118 32 0.049 0.108 35 0.077 0.04 37 0.004 0.028 38
<0.0005 0.013 39 0.004 0.008
Determination of Biomarker C-Myc and p21 in MV4-11 Cells.
[0372] MV4-11 cells were seeded in a 24-well plate at a density of
0.2.times.10.sup.6 cells/ml and incubated at 37.degree. C.
overnight. The cells were treated with the compounds at the
indicated concentrations and time points. The cells were harvested
at the indicated time points and protein extraction was performed
using the RIPA buffer. For the tumor samples, the protein was
extracted by homogenizing a small piece of the tumor in RIPA
buffer. 25-50 .mu.g protein was resolved in SDS-PAGE and subjected
to Western Blotting. The antibodies against cMYC and p21 were
purchased from Cell Signaling. The antibody against .beta.-Actin
was purchased from Sigma.
In Vivo Xenograft Model
[0373] The effects of the compounds to inhibit the growth of MV4-11
xenograft tumors were evaluated. Briefly, 5.times.10.sup.6 cells of
MV4-11 cells; diluted 1:1 with matrigel were injected
subcutaneously on the upper flanks of female nude mice (Charles
Rivers Labs). The total volume injected per animal was 200 .mu.L.
The mice were observed for approximately 15-20 days with
concomitant tumor volume measurement. The treatment was initiated
post-randomization when the average tumor volume was approximately
100 mm.sup.3. The compounds were formulated in 0.02% Tween-80, 0.5%
Methylcellulose and administered by oral gavage. The tumors were
measured by a pair of callipers thrice a week starting at the time
of size match, and tumor volumes were calculated according to the
formula V.dbd.(L.times.W.times.H).times.0.52 (V: volume, mm.sup.3;
L: length, mm; W: width, mm; H: height, mm) The tumor volume and
body weight were measured for the duration of the experiment, until
the mean tumor volume in each group reached an endpoint of >1000
mm.sup.3. Compounds of formula I showing greater 50% tumor growth
inhibition are considered as active.
[0374] Although the subject matter has been described in
considerable detail with reference to certain embodiments thereof,
other embodiments are possible. As such, the spirit and scope of
the invention should not be limited to the description of the
embodiments contained herein.
* * * * *